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Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19A Randomized Clinical Trial

Educational Objective
To understand the effects of hydrocortisone on 21-Day mortality or respiratory support among critically ill patients with COVID-19
1 Credit CME
Key Points

Question  Does low-dose hydrocortisone decrease treatment failure in patients with COVID-19–related acute respiratory failure?

Findings  In this randomized clinical trial that included 149 patients and was terminated early following the recommendation of the data and safety monitoring board, there was no significant difference in the rate of treatment failure (defined as death or persistent respiratory support with mechanical ventilation or high-flow oxygen therapy) on day 21 between the hydrocortisone and placebo groups (42.1% vs 50.7%, respectively).

Meaning  Low-dose hydrocortisone did not significantly reduce treatment failure in patients with COVID-19–related acute respiratory failure; however, the study was stopped early and was therefore likely underpowered.

Abstract

Importance  Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option.

Objective  To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure.

Design, Setting, and Participants  Multicenter randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19–related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board.

Interventions  Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73).

Main Outcomes and Measures  The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2 ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay.

Results  The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, –8.6% [95.48% CI, –24.9% to 7.7%]; P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment.

Conclusions and Relevance  In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome.

Trial Registration  ClinicalTrials.gov Identifier: NCT02517489

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Article Information

Corresponding Author: Pierre-François Dequin, MD, PhD, Service de Médecine Intensive–Réanimation, hôpital Bretonneau, 37044 Tours CEDEX 09, France (dequin@univ-tours.fr).

Accepted for Publication: August 18, 2020.

Published Online: September 2, 2020. doi:10.1001/jama.2020.16761

Author Contributions: Dr Dequin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Annane and Ms Le Gouge have contributed equally.

Concept and design: Dequin, Ehrmann, Tavernier, Zohar, Giraudeau, Le Gouge.

Acquisition, analysis, or interpretation of data: Dequin, Heming, Meziani, Plantefeve, Voiriot, Badie, François, Aubron, Ricard, Ehrmann, Jouan, Guillon, Leclerc, Coffre, Lengellé, Caille-Fenérol, Giraudeau, Annane, Le Gouge.

Drafting of the manuscript: Dequin.

Critical revision of the manuscript for important intellectual content: Dequin, Heming, Meziani, Plantefeve, Voiriot, Badie, François, Aubron, Ricard, Ehrmann, Jouan, Guillon, Leclerc, Coffre, Lengellé, Caille-Fenérol, Tavernier, Zohar, Giraudeau, Annane, Le Gouge.

Statistical analysis: Tavernier, Zohar, Giraudeau, Le Gouge.

Obtained funding: Dequin, Guillon, Annane.

Administrative, technical, or material support: Dequin, Badie, Aubron, Ehrmann, Jouan, Guillon, Leclerc, Caille-Fenérol.

Supervision: Dequin, Meziani.

Other - patient recruitment: Ricard.

Conflict of Interest Disclosures: Dr Dequin reported receiving grants from Abionic, Atox Bio, Sphingotec GMBH, Adrenomed, Medspace, Aridis, Merck, Combioxin, GlaxoSmithKline, MedImmune, Genentech INH, RevImmune, Faron, Kenta, and Tigenix. Dr Voiriot reported receiving personal fees from BioMérieux and receiving grants from BioMérieux, SOS Oxygène, and Janssen. Dr Ricard reported receiving grants from Fisher & Paykel. Dr Ehrmann reported receiving grants from Aerogen and Fisher & Paykel; personal fees from Aerogen and La Diffusion Technique Française; and nonfinancial support from Aerogen, Fisher & Paykel, and La Diffusion Technique Française. Dr Annane reported receiving a grant from the French Ministry of Health through the Programme National de Recherche Clinique to implement the REMAPCAP platform in France, which has a corticosteroid domain. No other authors reported disclosures.

Funding/Support: This study was funded by the French Ministry of Health, Programme Hospitalier de Recherche Clinique (PHRC) (2014 [CAPE COD parent trial], 2020 [CAPE COVID subtrial]).

Role of the Funder/Sponsor: The French Ministry of Health PHRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

CAPE COVID Trial Investigators: Pierre Moine, MD, PhD, Virginie Maxime, MD, Bernard Clair, MD, Rania Bounab, MD, Francesca Santi, MD, David Orlikowski, MD, PhD (Médecine Intensive Réanimation, Hôpital Raymond Poincaré, Garches, France); Julie Helms, MD, PhD, Raphaël Clere-Jehl, MD, Hassene Rahmani, MD, Alexandra Monnier, MD, Hamid Merdji, MD, Antoine Studer, MD, Jessy Cattelan, MD (Médecine Intensive Réanimation, Nouvel Hôpital Civil, Strasbourg, France); Laetitia Bodet-Contentin, MD, PhD, Walid Darwiche, MD, Denis Garot, MD, Annick Legras, MD, Stefan Mankikian, MD, Emmanuelle Mercier, MD, PhD, Marlène Morisseau, MD, Yonatan Perez, MD, Charlotte Salmon-Gandonnière, MD, PhD (Médecine Intensive-Réanimation, hôpital Bretonneau, Tours, France); Damien Contou, MD, Elsa Logre, MD, Radj Cally, MD, Mégan Fraisse, MD, Hervé Mentec, MD, Olivier Pajot, MD (Réanimation polyvalente, Hôpital Victor Dupouy, Argenteuil, France); Muriel Fartoukh, MD, PhD, Vincent Labbé, MD, Michel Djibré, MD, Aude Gibelin, MD, Clarisse Blayau, MD, Enora Berti, MD, Paris Meng, MD, Julien Lopinto, MD, Matthieu Turpin, MD, Alexandre Elabbadi, MD (Médecine Intensive Réanimation, Hôpital Tenon, Paris, France); Fernando Berdaguer-Ferrari, MD (Réanimation Polyvalente, Hôpital Nord Franche-Comté, Trevenans, France); Arnaud Desachy, MD, Guillaume Gilbert, MD, Marine Goudelin, MD, Bruno Evrard, MD, Thomas Daix, MD, Anne-Laure Fedou, MD, Philippe Vignon, MD, PhD (Réanimation Polyvalente, Hôpital Dupuytren, Limoges, France); Erwan L’Her, MD, PhD, Nicolas Ferrière, MD, Laetitia Bodenes, MD, Pierre Bailly, MD, Gwénaël Prat, MD, Jean-Marie Tonnelier, MD, Anne Renault, MD, Christelle Teiten, MD (Médecine Intensive Réanimation, Hôpital de la Cavale Blanche, Brest, France); Damien Roux, MD, PhD, Sébastien Besset, MD, Louis Marie Dumont, MD, Laura Fedirici, MD, Marc Amouretti, MD, Noémie Zucman, MD, Santiago Freita, MD, Didier Dreyfuss, MD, PhD (Médecine Intensive Réanimation, Hôpital Louis Mourier, Colombe, France). None of these individuals received compensation for their role in the study.

Members of the CRICS-TriGGERSep Network: See Supplement 3.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the members of the data and safety monitoring board for their commitment and responsiveness: Jean Chastre, MD (Assistance Publique–Hôpitaux de Paris, France); Béatrice Guyomarch, MSc (Centre Hospitalier Universitaire de Nantes, France); Liem Binh Luong Nguyen, MD, PhD (Assistance Publique–Hôpitaux de Paris, France); Sylvain Marchand-Adam, MD, PhD (Centre Hospitalier Universitaire de Tours, France); Véronique Sébille, PhD (Centre Hospitalier Universitaire de Nantes, France). None of these individals received compensation for their role in the study.

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