TY - JOUR
T1 - Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia
T2 - The COVID STEROID 2 Randomized Trial
AU - Munch, Marie W
AU - Myatra, Sheila N
AU - Vijayaraghavan, Bharath Kumar Tirupakuzhi
AU - Saseedharan, Sanjith
AU - Benfield, Thomas
AU - Wahlin, Rebecka R
AU - Rasmussen, Bodil S
AU - Andreasen, Anne Sofie
AU - Poulsen, Lone M
AU - Cioccari, Luca
AU - Khan, Mohd S
AU - Kapadia, Farhad
AU - Divatia, Jigeeshu V
AU - Brøchner, Anne C
AU - Bestle, Morten H
AU - Helleberg, Marie
AU - Michelsen, Jens
AU - Padmanaban, Ajay
AU - Bose, Neeta
AU - Møller, Anders
AU - Borawake, Kapil
AU - Kristiansen, Klaus T
AU - Shukla, Urvi
AU - Chew, Michelle S
AU - Dixit, Subhal
AU - Ulrik, Charlotte S
AU - Amin, Pravin R
AU - Chawla, Rajesh
AU - Wamberg, Christian A
AU - Shah, Mehul S
AU - Darfelt, Iben S
AU - Jørgensen, Vibeke L
AU - Smitt, Margit
AU - Granholm, Anders
AU - Kjær, Maj-Brit N
AU - Møller, Morten H
AU - Meyhoff, Tine S
AU - Vesterlund, Gitte K
AU - Hammond, Naomi E
AU - Micallef, Sharon
AU - Bassi, Abhinav
AU - Gluud, Christian
AU - Marcussen, Klaus V
AU - Nielsen, Henrik
AU - Schjørring, Olav L
AU - Kristensen, Camilla M
AU - Hjortsø, Carl J S
AU - Metcalf-Clausen, Matias
AU - Engstrøm, Janus
AU - Perner, Anders
AU - COVID STEROID 2 Trial Group
PY - 2021/11/9
Y1 - 2021/11/9
N2 - Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease.Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia.Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021.Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days.Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days).Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]).Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference.Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.
AB - Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease.Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia.Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021.Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days.Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days).Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]).Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference.Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.
KW - Aged
KW - COVID-19/complications
KW - Dexamethasone/administration & dosage
KW - Dose-Response Relationship, Drug
KW - Female
KW - Glucocorticoids/administration & dosage
KW - Humans
KW - Hypoxia/etiology
KW - Life Support Care
KW - Male
KW - Middle Aged
KW - Mycoses/etiology
KW - Respiration, Artificial
KW - Shock, Septic/etiology
KW - Single-Blind Method
UR - http://www.scopus.com/inward/record.url?scp=85117849363&partnerID=8YFLogxK
U2 - 10.1001/jama.2021.18295
DO - 10.1001/jama.2021.18295
M3 - Journal article
C2 - 34673895
SN - 0002-9955
VL - 326
SP - 1807
EP - 1817
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 18
M1 - 18295
ER -