Heterogeneity of treatment effect of higher dose dexamethasone by geographic region (Europe vs. India) in patients with COVID-19 and severe hypoxemia - a post hoc evaluation of the COVID STEROID 2 trial

Bharath Kumar Tirupakuzhi Vijayaraghavan; Anders Granholm; Sheila N Myatra; Vivekanand Jha; Naomi Hammond; Sharon Micallef; Marie Warrer Munch; Maj-Brit N Kjær; Morten Hylander Møller; Theis Lange; Anders Perner; Balasubramanian Venkatesh; COVID-STEROID 2 collaborators

doi:10.1016/j.lansea.2023.100293

Heterogeneity of treatment effect of higher dose dexamethasone by geographic region (Europe vs. India) in patients with COVID-19 and severe hypoxemia - a post hoc evaluation of the COVID STEROID 2 trial

Lancet Reg Health Southeast Asia. 2023 Oct 4:20:100293. doi: 10.1016/j.lansea.2023.100293. eCollection 2024 Jan.

Authors

Collaborators

COVID-STEROID 2 collaborators:
Marie W Munch, Sheila N Myatra, Bharath Kumar Tirupakuzhi Vijayaraghavan, Sanjith Saseedharan, Thomas Benfield, Rebecka R Wahlin, Bodil S Rasmussen, Anne Sofie Andreasen, Lone M Poulsen, Luca Cioccari, Mohd S Khan, Farhad Kapadia, Jigeeshu V Divatia, Anne C Brøchner, Morten H Bestle, Marie Helleberg, Jens Michelsen, Ajay Padmanaban, Neeta Bose, Anders Møller, Kapil Borawake, Klaus T Kristiansen, Urvi Shukla, Michelle S Chew, Subhal Dixit, Charlotte S Ulrik, Pravin R Amin, Rajesh Chawla, Christian A Wamberg, Mehul S Shah, Iben S Darfelt, Vibeke L Jørgensen, Margit Smitt, Anders Granholm, Maj-Brit N Kjær, Morten H Møller, Tine S Meyhoff, Gitte K Vesterlund, Naomi E Hammond, Sharon Micallef, Abhinav Bassi, Oommen John, Anubhuti Jha, Maria Cronhjort, Stephan M Jakob, Christian Gluud, Theis Lange, Vaijayanti Kadam, Klaus V Marcussen, Jacob Hollenberg, Anders Hedman, Henrik Nielsen, Olav L Schjørring, Marie Q Jensen, Jens W Leistner, Trine B Jonassen, Camilla M Kristensen, Esben C Clapp, Carl Js Hjortsø, Thomas S Jensen, Liv S Halstad, Emilie Rb Bak, Reem Zaabalawi, Matias Metcalf-Clausen, Suhayb Abdi, Emma V Hatley, Tobias S Aksnes, Emil Gleipner-Andersen, A Felix Alarcón, Gabriel Yamin, Adam Heymowski, Anton Berggren, Kirstine la Cour, Sarah Weihe, Alison H Pind, Janus Engstrøm, Vivekanand Jha, Balasubramanian Venkatesh, Anders Perner

Affiliations

¹ Department of Critical Care Medicine, Apollo Hospitals, Chennai, India.
² Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet, Denmark.
³ Department of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India.
⁴ The George Institute for Global Health, New Delhi, India.
⁵ Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India.
⁶ School of Public Health, Imperial College London, United Kingdom.
⁷ Critical Care Program, The George Institute for Global Health, University of New South Wales, Australia.
⁸ Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia.
⁹ Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark.

Abstract

Background: In the COVID-STEROID 2 trial there was suggestion of heterogeneity of treatment effects (HTE) between patients enrolled from Europe vs. India on the primary outcome. Whether there was HTE for the remaining patient-centred outcomes is unclear.

Methods: In this post hoc analysis of the COVID-STEROID 2 trial, which compared 12 mg vs. 6 mg dexamethasone in adults with COVID-19 and severe hypoxemia, we evaluated HTE by geographical region (Europe vs. India) for secondary outcomes with analyses adjusted for stratification variables. Results are presented as risk differences (RDs) or mean differences (MDs) with 99% confidence intervals (CIs) and P-values from interaction tests.

Findings: There were differences in mortality at day 28 (RD for Europe -8.3% (99% CI: -17.7 to 1.0) vs. India 0.1% (99% CI: -10.0 to 10.0)), mortality at day 90 (RD for Europe -7.4% (99% CI: -17.1 to 2.0) vs. India -1.4% (99% CI: -12.8 to 9.8)), mortality at day 180 (RD for Europe -6.7% (99% CI: -16.4 to 2.9) vs. India -1.0% (99% CI: -12.3 to 10.3)), and number of days alive without life support at day 90 (MD for Europe 6.1 days (99% CI: -1.3 to 13.4) vs. India 1.7 days (99% CI: -8.4 to 11.8)). For serious adverse reactions, the direction was reversed (RD for Europe -1.0% (99% CI: -7.1 to 5.2) vs. India -5.3% (99% CI: -16.2 to 5.0).

Interpretation: Our analysis suggests higher dose dexamethasone may have less beneficial effects for patients in India as compared with those in Europe; however, the evidence is weak, and this could represent a chance finding.

Funding: None for this analysis. The COVID STEROID 2 trial was funded by The Novo Nordisk Foundation and supported by Rigshospitalet's Research Council.

Keywords: COVID-19; Developing countries; Randomised controlled trials; Steroids.