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    1 Comment for this article
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    The potent effect of a press release: Dangerous precedence during dangerous times.... and beyond
    Shyan Goh, MBBS, FRACS | Private
    This paper by CAPE COVID researchers reflects issues related to providing evidence by press release. Their trial was prematurely stopped (at 149 patients out of the 290, between March 7 and June 1, 2020) after the press release of the RECOVERY trial (June 16)(1).

    This decision was apparently made on the basis of what is available in that press release; the preprint and final published version (in NEJM) from the RECOVERY group regarding dexamethasone (DEXA) was not available until June 22 (2) and July 17 2020 (3) respectively, whereas the last followup by COPE COVID was on 29 June
    2020.

    Whilst some can attest that researchers, in the conduct of their study, should not be influenced by press release or papers not peer-reviewed, this is a clear example of real-world dynamics, when researchers are also clinicians involved in the care of patients with a newly discovered high-profile infection with a high mortality rate, facing the potential pressure of the general public why their loved ones should participate in a randomised (placebo-) controlled trial when news of a miracle cure is reverberating around the world by press release.

    Does hydrocortisone (HC) reduce mortality in critically ill COVID-19 patients? The researchers can speculate, the WHO can extrapolate it is a "class effect" (which I do not necessarily concur with based on available evidence) (4) but I suspect we may never really know.

    I fear that this heralds the beginning of a new era of "trial by media" in medical research, when combined with "cancel culture" poses new obstacles in the conduct of research.

    The announcements by RECOVERY may offer a good step forward in the right direction for COVID-19 pandemic, but its long-lasting effect is three step backwards for the future of evidence-based medicine.

    References
    1. https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19
    2. https://doi.org/10.1101/2020.06.22.20137273
    3. NEJM. doi:10.1056/NEJMoa2021436
    4. JAMA. doi:10.1001/jama.2020.17023
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    Caring for the Critically Ill Patient
    September 2, 2020

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

    Author Affiliations
    • 1Médecine Intensive-Réanimation, CHU de Tours, Tours, France
    • 2INSERM U1100, Centre d'Etude des Pathologies Respiratoires, Université de Tours, Tours, France
    • 3INSERM CIC1415, CHU de Tours, Tours, France
    • 4Médecine Intensive Réanimation, Hôpital Raymond Poincaré (GHU APHP Université Paris Saclay), Garches, France, and RHU RECORDS and FHU SEPSIS
    • 5INSERM U1173, Université de Versailles SQY-Université Paris Saclay, Garches, France
    • 6Médecine Intensive Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
    • 7INSERM UMR 1260, Université de Strasbourg, Strasbourg, France
    • 8Réanimation polyvalente, CH Victor Dupouy, Argenteuil, France
    • 9Médecine Intensive Réanimation, Hôpital Tenon (Assistance Publique–Hôpitaux de Paris), Paris, France
    • 10Sorbonne Université, Paris, France
    • 11Réanimation Polyvalente, Hôpital Nord Franche-Comté, Trevenans, France
    • 12Réanimation Polyvalente, CHU de Limoges, Limoges, France
    • 13INSERM UMR 1092, Université de Limoges, Limoges, France
    • 14INSERM CIC 1435, CHU de Limoges, Limoges, France
    • 15Médecine Intensive Réanimation, CHRU de Brest, Brest, France
    • 16Université de Bretagne Occidentale, Brest, France
    • 17Université de Paris, IAME U1137, Médecine Intensive Réanimation, DMU ESPRIT, Hôpital Louis Mourier, Assistance Publique–Hôpitaux de Paris, Colombe, France
    • 18Délégation à la Recherche Clinique et à l’Innovation, CHU de Tours, Tours, France
    • 19Pharmacie à Usage Interne, CHU de Tours, Tours, France
    • 20Centre régional de pharmacovigilance et d'information sur le médicament, service de pharmacosurveillance, CHU de Tours, Tours, France
    • 21INSERM, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France
    • 22Université de Tours, Université de Nantes, INSERM, SPHERE U1246, Tours, France
    JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.16761
    Visual Abstract. Effect of Hydrocortisone on Mortality and Respiratory Support in Critically Ill Patients With COVID-19
    Effect of Hydrocortisone on Mortality and Respiratory Support in Critically Ill Patients With COVID-19
    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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