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JAMA
. 2020 Sep 2.
doi: 10.1001/jama.2020.17022. Online ahead of print.
Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial
Writing Committee for the REMAP-CAP Investigators; Derek C Angus 1 2 , Lennie Derde 3 4 , Farah Al-Beidh 5 , Djillali Annane 6 7 8 , Yaseen Arabi 9 , Abigail Beane 10 , Wilma van Bentum-Puijk 3 , Lindsay Berry 11 , Zahra Bhimani 12 , Marc Bonten 3 13 , Charlotte Bradbury 14 15 , Frank Brunkhorst 16 , Meredith Buxton 17 , Adrian Buzgau 18 , Allen C Cheng 19 20 , Menno de Jong 21 , Michelle Detry 11 , Lise Estcourt 22 23 , Mark Fitzgerald 11 , Herman Goossens 24 , Cameron Green 20 , Rashan Haniffa 25 26 , Alisa M Higgins 20 , Christopher Horvat 1 2 , Sebastiaan J Hullegie 3 , Peter Kruger 27 , Francois Lamontagne 28 , Patrick R Lawler 29 , Kelsey Linstrum 1 , Edward Litton 30 , Elizabeth Lorenzi 11 , John Marshall 12 31 , Daniel McAuley 32 , Anna McGlothin 11 , Shay McGuinness 20 33 34 , Bryan McVerry 35 , Stephanie Montgomery 1 2 , Paul Mouncey 36 , Srinivas Murthy 37 , Alistair Nichol 20 38 39 40 , Rachael Parke 33 34 41 , Jane Parker 20 , Kathryn Rowan 36 , Ashish Sanil 11 , Marlene Santos 12 , Christina Saunders 11 , Christopher Seymour 1 2 , Anne Turner 34 , Frank van de Veerdonk 42 , Balasubramanian Venkatesh 43 44 , Ryan Zarychanski 45 , Scott Berry 11 , Roger J Lewis 11 46 47 , Colin McArthur 36 48 , Steven A Webb 20 30 49 , Anthony C Gordon 5
Affiliations
- PMID: 32876697
- DOI: 10.1001/jama.2020.17022
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.