TY - JOUR
T1 - Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia
T2 - a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial
AU - Granholm, Anders
AU - Munch, Marie Warrer
AU - Myatra, Sheila Nainan
AU - Vijayaraghavan, Bharath Kumar Tirupakuzhi
AU - Cronhjort, Maria
AU - Wahlin, Rebecka Rubenson
AU - Jakob, Stephan M.
AU - Cioccari, Luca
AU - Kjær, Maj Brit Nørregaard
AU - Vesterlund, Gitte Kingo
AU - Meyhoff, Tine Sylvest
AU - Helleberg, Marie
AU - Møller, Morten Hylander
AU - Benfield, Thomas
AU - Venkatesh, Balasubramanian
AU - Hammond, Naomi E.
AU - Micallef, Sharon
AU - Bassi, Abhinav
AU - John, Oommen
AU - Jha, Vivekanand
AU - Kristiansen, Klaus Tjelle
AU - Ulrik, Charlotte Suppli
AU - Jørgensen, Vibeke Lind
AU - Smitt, Margit
AU - Bestle, Morten H.
AU - Andreasen, Anne Sofie
AU - Poulsen, Lone Musaeus
AU - Rasmussen, Bodil Steen
AU - Brøchner, Anne Craveiro
AU - Strøm, Thomas
AU - Møller, Anders
AU - Khan, Mohd Saif
AU - Padmanaban, Ajay
AU - Divatia, Jigeeshu Vasishtha
AU - Saseedharan, Sanjith
AU - Borawake, Kapil
AU - Kapadia, Farhad
AU - Dixit, Subhal
AU - Chawla, Rajesh
AU - Shukla, Urvi
AU - Amin, Pravin
AU - Chew, Michelle S.
AU - Wamberg, Christian Aage
AU - Gluud, Christian
AU - Lange, Theis
AU - Perner, Anders
N1 - Funding Information:
AG, MWM, MBNK, GKV, TSM, MHM and AP are affiliated with the Department of Intensive Care at Rigshospitalet, University of Copenhagen, which has received grants from the Novo Nordisk Foundation during the conduct of the trial; and grants from Pfizer, Fresenius Kabi, The Novo Nordisk Foundation, and Sygeforsikringen “danmark” outside the submitted work. SMJ and LC are affiliated with Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland, which has received grants from Edwards Lifesciences Services GmbH, Phagenesis Limited, and Nestlé; all outside the submitted work. TB has received grants from the Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Hansen Foundation, and Erik and Susanna Olesen’s Charitable Fund; grants and personal fees from GSK, Pfizer, and Gilead; personal fees from Boehringer Ingelheim, MSD, and Pentabase ApS; all outside the submitted work. BV and NEH have received grants from Baxter outside the submitted work. VJ has received grants and personal fees from Baxter Healthcare; personal fees from Astra Zeneca, Visterra, Chinook, and NephroPlus; all outside the submitted work. CSU has received grants and personal fees from GSK, Sanofi Genzyme, Astra Zeneca, Teva, OrionPharma, Boehringer-Ingelheim, Actelion and Chiesi; grants, personal fees and non-financial support from Novartis; all outside the submitted work.JVD has received personal fees (paid to his institution) from Edwards India outside the submitted work. PA has received personal fees from CIPLA, Dr. Reddy’s Laboratories, Abbott Nutrition and Sanofi; all outside the submitted work. The remaining authors declared no known conflicts of interest.
Funding Information:
The COVID STEROID 2 trial was funded by the Novo Nordisk Foundation (grant number 0062998) and supported by Rigshospitalet’s Research Council (E-22703–06). None of the funders had any influence on trial design, conduct, analysis, or decision to report. AG’s salary is paid by a grant from Sygeforsikringen “danmark”, which had no influence on this trial.
Publisher Copyright:
© 2021, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022/1
Y1 - 2022/1
N2 - Purpose: We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. Methods: We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. Results: The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI −0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. Conclusion: We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.
AB - Purpose: We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. Methods: We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. Results: The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI −0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. Conclusion: We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.
KW - Bayesian analysis
KW - Corticosteroids
KW - COVID-19
KW - Critical illness
KW - Hypoxaemia
KW - SARS-CoV-2
KW - Dexamethasone
KW - COVID-19/drug therapy
KW - Humans
KW - Bayes Theorem
KW - Hypoxia
KW - Steroids
U2 - 10.1007/s00134-021-06573-1
DO - 10.1007/s00134-021-06573-1
M3 - Journal article
C2 - 34757439
AN - SCOPUS:85118888068
VL - 48
SP - 45
EP - 55
JO - Intensive Care Medicine
JF - Intensive Care Medicine
SN - 0342-4642
IS - 1
ER -