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September - 2020

   

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

The Writing Committee for the REMAP-CAP Investigators JAMA, 2020, online Sept 2020

Comment

This is an important trial for a number of reasons. Firstly, it reports the effect of hydrocortisone in COVI-19. Secondly, it is the first publication from REMAP-CAP, an adaptive Bayesian platform trial

In July the RECOVERY trial reported https://www.crit-iq.com/index.php/Library/Review/1474/Dexamethasone-Hospitalized-Covid-19-mortality-critical-intensive-mechanical-ventilation the preliminary results of the dexamethasone arm of their trial. In 2104 patients, dexamethasone 6mg daily for up to 10-days vs placebo in hospitalised patients with COVID-19 was associated with lower 28-day mortality compared to usual care. This effect was greatest in patients receiving mechanical ventilation at the time of enrolment, and there was no benefit in patients requiring no respiratory support (O2, IMV) at enrolment. The cohort of “sicker” patients with greatest benefit were younger, and had a longer duration of symptom prior to enrolment.

The details of the REMAP-CAP trial overall;

  • “ongoing, international, multicenter, open label, trial that combines features of an adaptive platform trial with a pragmatic point-of-care trial to determine best treatment strategies for patients with severe pneumonia in both pandemic and nonpandemic settings”; 
    • randomization, allowing causal inference
    • embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, generalizability
    • a multifactorial statistical model comparing multiple interventions across multiple patient subgroups
    • response-adaptive randomization with preferential assignment to those interventions that appear most favorable after interim analyses
    • and a platform structured to permit continuous, potentially perpetual, enrollment
  • The trial randomises patients to multiple interventions within multiple domains, evaluating effectiveness within different patient strata. The term domain refers to a common therapeutic area (eg, antiviral therapy or immunoglobulin therapy) within which several interventions or intervention dosing strategies can be randomly assigned (including a control, such as no antiviral, as appropriate).
  • A COVID-19 stratum was added Jan 31, 2020;
    • Classified as moderate or severely ill
    • COVID-19 specific domains: antiviral, corticosteroid, targeted immune modulation, immunoglobulin, and therapeutic anticoagulation

The details of the REMAP-CAP COVID-19 Corticosteroid Domain

  • Adults, presume for confirmed SARS-CoV-2 infection, admitted to ICU for provision of respiratory or cardiovascular organ support
  • Hydrocortisone intervention- fixed dose and shock dependent hydrocortisone interventions. Randomised 1:1 or 1:1:1 depending in site a priori assignment 
    • IV HC 50mg QID 7-days
    • IV HC 50mg QID while in shock for up to 28-days
    • IV HC 100mg QID 7-days was being incorporated when randomisation stopped, so only 2 assigned. 
    • No hydrocortisone 
  • Statistical analysis
    • No sample size given uncertainty about pandemic. If both hydrocortisone groups had effect sizes (odds ratios) of 1.75 compared with the no hydrocortisone group, there would be 90% power to determine whether either group was superior to the no hydrocortisone group with a sample size of 500 patients. If the effect was 1.5, there would be 90% power with a sample size of 1000 patients. 
    • Analysis Plan: Bayesian cumulative logistic model, which estimated posterior probability distributions of the 21-day organ support–free days (primary outcome) based on the evidence accumulated in the trial from UK ICNARC data. The 2 HC arms were initially analysed together
  • In total 403 participants enrolled, and trial stopped early die to RECOVERY results. 
  • Baseline: Matched, approx 60-years age, 59-64% ventilated on enrolment
  • Intervention;
    • HC 7-day: 93% received 1st dose, median duration 7-days
    • HC shock : 43% received 1st dose, median duration 3-days
    • No HC: 15% received corticosteroid. 
  • Primary outcome: 
    • Respiratory and cardiovascular organ support free-days up to day 21 (ordinal end-point with death as worst outcome, 21 organ fee days as best). 
    • HC 7-day median OSFD 0 [-1, 15]
    • HC shock 0 [-1,13]
    • No HC 0 [-1,11]
    • Compared to no hydrocortisone, probability of improvement in 21-day organ support- free days was hydrocortisone (7-day) 93% (OR 1.43, 95% CI 0.91-2.227) vs and shock reversal 80% (OR 1.22, 95% CI 0.76-1.94)
    • Stopped early, and no treatment met pre-specified criteria for superiority.
  • Secondary outcomes: No difference in-hospital mortality, ICU and hospital LOS, individual organ support free days, ECMO or death.
    • Hospital mortality 30%(HC 7) vs 26% (HC shock) vs 33% (no HC)
  • No sample  

Overall “The principal findings from this study were a 93% probability of benefit of a fixed-duration dosing of hydrocortisone and an 80% probability of benefit of a shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, with regard to the odds of improvement in organ support–free days within 21 days”. However, the trial was stopped early, and these did not reach statistical significance, 15% of the no hydrocortisone arm received hydrocortisone. Perhaps it simply supports the RECOVERY trial results  

 

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.

September


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