Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial,Intensive Care Medicine

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Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial
Intensive Care Medicine ( IF 27.1 ) Pub Date : 2021-11-10 , DOI: 10.1007/s00134-021-06573-1
Anders Granholm _{1,

2} , Marie Warrer Munch _{1,

2} , Sheila Nainan Myatra ₃ , Bharath Kumar Tirupakuzhi Vijayaraghavan _{4,

5,

6} , Maria Cronhjort ₇ , Rebecka Rubenson Wahlin ₇ , Stephan M Jakob ₈ , Luca Cioccari ₈ , Maj-Brit Nørregaard Kjær _{1,

2} , Gitte Kingo Vesterlund _{1,

2} , Tine Sylvest Meyhoff _{1,

2} , Marie Helleberg ₉ , Morten Hylander Møller _{1,

2} , Thomas Benfield ₁₀ , Balasubramanian Venkatesh ₁₁ , Naomi E Hammond _{11,

12} , Sharon Micallef ₁₁ , Abhinav Bassi ₆ , Oommen John _{6,

13} , Vivekanand Jha _{6,

13,

14} , Klaus Tjelle Kristiansen ₁₅ , Charlotte Suppli Ulrik ₁₆ , Vibeke Lind Jørgensen ₁₇ , Margit Smitt ₁₈ , Morten H Bestle _{19,

20} , Anne Sofie Andreasen ₂₁ , Lone Musaeus Poulsen ₂₂ , Bodil Steen Rasmussen _{2,

23} , Anne Craveiro Brøchner _{2,

24} , Thomas Strøm _{25,

26} , Anders Møller ₂₇ , Mohd Saif Khan ₂₈ , Ajay Padmanaban ₄ , Jigeeshu Vasishtha Divatia ₃ , Sanjith Saseedharan ₂₉ , Kapil Borawake ₃₀ , Farhad Kapadia ₃₁ , Subhal Dixit ₃₂ , Rajesh Chawla ₃₃ , Urvi Shukla ₃₄ , Pravin Amin ₃₅ , Michelle S Chew ₃₆ , Christian Aage Wamberg ₃₇ , Christian Gluud _{38,

39} , Theis Lange ₄₀ , Anders Perner _{1,

2}

Affiliation

Department of Intensive Care, Rigshospitalet-Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.
Collaboration for Research in Intensive Care (CRIC), Copenhagen, Denmark.
Department of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India.
Department of Critical Care, Apollo Hospitals, Chennai, India.
Chennai Critical Care Consultants, Chennai, India.
The George Institute for Global Health, New Delhi, India.
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Center of Research & Disruption of Infectious Diseases, Department of Infectious Diseases, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark.
The George Institute for Global Health, University of New South Wales, Sydney, Australia.
Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia.
Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India.
School of Public Health, Imperial College London, London, UK.
Department of Anaesthesia and Intensive Care, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
Department of Respiratory Medicine, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark.
Department of Thoracic Anaesthesiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Department of Neuroanaesthesiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Department of Anaesthesia and Intensive Care, Copenhagen University Hospital - North Zealand, Hillerød, Denmark.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Department of Anaesthesia and Intensive Care, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
Department of Anaesthesiology, Zealand University Hospital, Køge, Denmark.
Department of Anaesthesia and Intensive Care, Aalborg University Hospital, Aalborg, Denmark.
Department of Anaesthesia and Intensive Care, Kolding Hospital, University Hospital of Southern Denmark, Kolding, Denmark.
Department of Anaesthesia and Critical Care Medicine, Odense University Hospital, Odense C, Denmark.
Department of Anaesthesia and Critical Care Medicine, Hospital Sønderjylland, University Hospital of Southern, Odense, Denmark.
Department of Anaesthesia and Intensive Care, Næstved-Slagelse-Ringsted Hospital, Slagelse, Denmark.
Department of Critical Care Medicine, Rajendra Institute of Medical Sciences, Ranchi, India.
Department of Intensive Care, SL Raheja Hospital, Mumbai, Maharashtra, India.
Department of Intensive Care, Vishwaraj Hospital, Pune, India.
Section of Critical Care, Department of Medicine, Hinduja Hospital, Mahim, Mumbai, India.
Department of Critical Care Medicine, Sanjeevan Hospital, Pune, Maharashtra, India.
Department of Respiratory and Critical Care Medicine, Indraprastha Apollo Hospital, New Delhi, India.
Intensive Care Unit and Emergency Services, Symbiosis University Hospital and Research Centre, Lavale, Pune, India.
Department of Critical Care Medicine, Bombay Hospital Institute of Medical Sciences, Mumbai, India.
Department of Anesthesiology and Intensive Care, Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Department of Anaesthesia and Intensive Care, Bispebjerg Hospital, Copenhagen, Denmark.
Centre for Clinical Intervention Research, Copenhagen Trial Unit, Capital Region of Denmark, Copenhagen University Hospital -Rigshospitalet, Copenhagen, Denmark.
Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark.

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.

中文翻译：

地塞米松 12 mg 与 6 mg 用于治疗 COVID-19 和严重低氧血症的患者：对 COVID STEROID 2 试验进行预先计划的二次贝叶斯分析

目的

我们在国际随机、盲法 COVID STEROID 2 试验中，对 2019 年冠状病毒病 (COVID-19) 和严重低氧血症患者每天服用 12 毫克地塞米松与服用 6 毫克地塞米松长达 10 天进行了比较。在主要的常规分析中，未达到预定义的统计显着性阈值。我们进行了预先计划的贝叶斯分析以促进概率解释。

方法

我们使用贝叶斯模型和各种敏感性分析，分析了意向治疗人群 90 天内的结果数据（数据来自 967 至 982 名患者）。结果以 95% 可信区间 (CrIs) 的中后验概率和 12 mg 地塞米松不同效应大小的概率表示。

结果

第 28 天无生命支持的存活天数（主要结果）的调整后平均差异为 1.3 天（95% CrI -0.3 至 2.9；受益概率为 94.2%）。调整后的严重不良反应相对风险和获益概率为0.85（0.63至1.16；84.1%），第28天死亡率为0.87（0.73至1.03；94.8%），第90天为0.88（0.75至1.02；95.1%）。没有生命支持的存活天数和第 90 天出院存活天数的获益概率分别为 85% 和 95.7%。敏感性分析的结果基本一致，所有分析中所有结果的 12 mg 造成临床重要危害的可能性相对较低。