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

Derek Angus*, Charlotte A Bradbury

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

IMPORTANCE Evidence regarding corticosteroid use for severe 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. Between March 9 and June 17th 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least one 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 12th, 2020. INTERVENTIONS The Corticosteroid Domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50mg or 100mg q6h) (n=143), a shock-dependent course (50mg q6h 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, OSFDs) within 21 days, where patients who died were assigned –1 days. 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 expressed as the posterior probability (%) of OR >1 (threshold for trial conclusion: >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. The median (IQR) OSFDs were 0 (–1, 15), 0 (–1, 13) and 0 (–1, 11) days (composed of 30%, 26% and 33% mortality rates and 11.5, 9.5 and 6 median OSFDs among survivors) for the fixed dose, shock-dependent, and no hydrocortisone groups, respectively. The adjusted OR (median, 95% credible interval) and Bayesian probability of superiority (%) was 1.43 (0.91 – 2.27) and 93% for fixed dose hydrocortisone and 1.22 (0.76 – 1.94) and 80% for shock-dependent hydrocortisone compared to 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, precluding definitive conclusions. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT02735707
Original languageEnglish
Pages (from-to)1317-1329
Number of pages13
JournalJAMA - Journal of the American Medical Association
Volume324
Issue number13
Early online date2 Sep 2020
DOIs
Publication statusE-pub ahead of print - 2 Sep 2020

Structured keywords

  • Covid19
  • UNCOVER

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