Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19 AMeta-analysis

In this prospective meta-analysis of 7 randomized trials that included 1703 patients of whom 647 died, 28-day all-cause mortality was lower among patients who received corticosteroids compared with those who received usual care or placebo (summary odds ratio, 0.66).

Year: 2020
Author: The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group
Journal: JAMA

IMPORTANCE Effective therapies for patients with coronavirus disease 2019 (COVID-19) are
needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced
mortality in hospitalized patients with COVID-19 who required respiratory support.
OBJECTIVE To estimate the association between administration of corticosteroids compared
with usual care or placebo and 28-day all-cause mortality.
DESIGN, SETTING, AND PARTICIPANTS Prospectivemeta-analysis that pooled data from 7
randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill
patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to
June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated
from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed
using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was
assessed using the I2 statistic. The primary analysis was an inverse variance–weighted
fixed-effectmeta-analysis of overall mortality, with the association between the intervention
and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were
conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp
adjustment) and an inverse variance–weighted fixed-effect analysis using risk ratios.

About

UMC Utrecht is the Sponsor for the trial in Europe and some countries outside Europe.

Contact

University Medical Center Utrecht
Heidelberglaan 100
3584 CX Utrecht
The Netherlands

Email:
EU.remapcap@umcutrecht.nl

Registration

REMAP-CAP ClinicalTrials.gov registration NCT02735707

REMAP-CAP EU Clinical Trials Register EUCT number: 2023-507889-89

Funding

REMAP-CAP is supported by the ECRAID-Base project which has received funding from the EU Horizon 2020 research and innovation programme (grant number 965313).

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Summary of platform conclusions

Inseparable to the design of this trial, platform conclusions are generated through frequent adaptive analyses as data accrues. To date, REMAP-CAP has contributed to the knowledge about the best treatment of COVID-19 with several results:

ACE2 RAS DOMAIN (27 Feb 2022)

- After interim review of safety data, the Data safety and Monitoring Board recomended stopping enrolment of critically ill patients into the domain, which is in phase 2. Enrolment of criticall and non-critically patients was stopped pending review of additional data.

Antiplatelet DOMAIN (23 Jun 2021)

- Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared
  with no antiplatelet agent, had a low likelihood of providing improvement in the number of
  organ support–free days within 21 days. However, when looking at survival on its own we saw that both aspirin and clopidogrel may improve survival. Published in the Journal of the American Medical Association (7). Domain revised and continued for non-critically ill ptients.

CORTICOSTEROID DOMAIN

Glucocorticoids improve outcomes for hospitalized patients with COVID-19. Published in the Journal of the American Medical Association (1). Results also included in the WHO meta-analysis published in JAMA on the same day (2).

COVID-19 IMMUNE MODULATION DOMAIN

Tocilizumab and sarilumab reduce mortality and prevent progression to invasive mechanical ventilation or ECMO in critically ill patients with COVID-19. Results published in the New England Journal of Medicine (5).
Tocilizumab and Sarilumab have reached the statistical trigger for equivalence and are the best interventions in the domain. This domain is paused while the full analysis of all interventions included in this domain, including Anakinra and Interferon-β1a, is being completed.

COVID-19 ANTI-COAGULATION DOMAIN

Therapeutic anticoagulation is futile, and possibly harmful, in critically ill patients with COVID-19. Conclusion from the multi-platform RCT collaboration between REMAP-CAP ATTACC and ACTIV-4, pre-print available from MedRxiv (3)
Therapeutic anticoagulation improves outcomes in hospitalized patients with COVID-19 who are not admitted to an ICU with organ support. Conclusion from the multi-platform RCT collaboration between REMAP-CAP, ATTACC and ACTIV-4, pre-print available from MedRxiv (4).

COVID-19 IMMUNOGLOBULIN DOMAIN

Convalescent plasma does not improve outcomes for critically ill patients with COVID-19. Shortly after this REMAP-CAP platform conclusion, the RECOVERY trial announced no significant difference in 28-day mortality in that trial. In light of these results, the REMAP-CAP ITSC decided to pause recruitment in the Moderate State of this domain.

COVID-19 ANTIVIRAL DOMAIN

Lopinavir/ritonavir does not improve outcomes for critically ill patients with COVID-19. The manuscript is in preparation.
Hydroxychloroquine does not improve outcomes, and potentially harms patients with COVID-19. Results available in a collaborative meta-analysis as a preprint (6).

1. Angus DC, Derde L, Al-Beidh F, Annane D, Arabi Y, Beane A, et al. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. Jama. 2020;324(13):1317-29.

2. The WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020;324(13):1330-41.

3. The REMAP-CAP, ACTIV4-a, ATTACC Investigators, Zarychanski R. Therapeutic Anticoagulation in Critically Ill Patients with Covid-19 – Preliminary Report. medRxiv. 2021:2021.03.10.21252749.

4. Lawler PR, Goligher EC, Berger JS, Neal MD, McVerry BJ, Nicolau JC, et al. Therapeutic Anticoagulation in Non-Critically Ill Patients with Covid-19. medRxiv. 2021:2021.05.13.21256846.

5. The REMAP-CAP Investigators. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. New England Journal of Medicine. 2021;384(16):1491-502.

6. Axfors C, Schmitt AM, Janiaud P, Van’t Hooft J, Abd-Elsalam S, Abdo EF, et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nat Commun. 2021;12(1):2349.

7. REMAP-CAP Writing Committee for REMAP-CAP Investigators. Effect of Antiplatelet on Survival and Organ Support-Free Days in Critically ill patients with COVID-19. JAMA. 2022;327(13):1247-1259. doi:10.1001/jama.2022.2910fter interim