Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial

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 relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Trial registration: ClinicalTrials.gov Identifier: NCT02735707.

Figure 1.. Screening, Randomization, and Follow-up of Participants in the REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial

COVID-19 indicates coronavirus disease 2019; ICU, intensive care unit; and REMAP-CAP, Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia. ^aPatients could meet more than 1 ineligibility criterion. ^bThe primary analysis of alternative interventions within the corticosteroid domain is estimated from a model that adjusts for patient factors and for assignment to interventions in other domains. To obtain the most reliable estimation of the effect of these patient factors and of other interventions on the primary outcome, all patients enrolled in the severe COVID-19 cohort (for whom there is consent and follow-up) are included. Importantly, however, the model also factors eligibility for the corticosteroid domain and its interventions, such that the final estimate of a corticosteroid domain intervention’s effectiveness relative to any other within that domain is generated from those patients that might have been randomized to either.

Figure 2.. Organ Support–Free Days

A, Distributions of organ support–free days (see the Methods section for definition) by study group as the cumulative proportion (y-axis) for each study group by day (x-axis), with death listed first. Curves that rise more slowly are more favorable. B, Organ support–free days as horizontally stacked proportions by study group. Red represents worse values and blue represents better values. The median adjusted odds ratios from the primary analysis, using a bayesian cumulative logistic model, were 1.43 (95% credible interval, 0.91-2.27) and 1.22 (95% credible interval, 0.76-1.94) for the fixed-dose and shock-dependent hydrocortisone groups compared with the no hydrocortisone group, yielding 93% and 80% probabilities of superiority over the no hydrocortisone group, respectively.