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; Marie W. Munch; Maj Brit N. Kjær; Morten H. Møller; Anders Perner; Sheila N. Myatra; Vivekanand Jha; Vivekanand Jha; Vivekanand Jha; Naomi Hammond; Sharon Micallef; Balasubramanian Venkatesh; Naomi Hammond; Theis Lange; 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; Charlotte S. Ulrik; Maj Brit N. Kjær; Morten H. Møller; Tine S. Meyhoff; Gitte K. Vesterlund; Christian Gluud; Theis Lange; Klaus V. Marcussen; Henrik Nielsen; Thomas S. Jensen; Anders Perner; the 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

Bharath Kumar Tirupakuzhi Vijayaraghavan, Anders Granholm, Marie W. Munch, Maj Brit N. Kjær, Morten H. Møller, Anders Perner, Sheila N. Myatra, Vivekanand Jha, Vivekanand Jha, Vivekanand Jha, Naomi Hammond, Sharon Micallef, Balasubramanian Venkatesh, Naomi Hammond, Theis Lange, Marie W. Munch, Sheila N. Myatra, Bharath Kumar Tirupakuzhi Vijayaraghavan, Sanjith Saseedharan, Thomas BenfieldRebecka 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, Charlotte S. Ulrik, Maj Brit N. Kjær, Morten H. Møller, Tine S. Meyhoff, Gitte K. Vesterlund, Christian Gluud, Theis Lange, Klaus V. Marcussen, Henrik Nielsen, Thomas S. Jensen, Anders Perner, the COVID-STEROID 2 collaborators

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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.

Original language	English
Article number	100293
Journal	The Lancet Regional Health - Southeast Asia
Volume	20
Number of pages	8
DOIs	https://doi.org/10.1016/j.lansea.2023.100293
Publication status	Published - 2024

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Keywords

COVID-19
Developing countries
Randomised controlled trials
Steroids

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Tirupakuzhi Vijayaraghavan, B. K., Granholm, A., Munch, M. W., Kjær, M. B. N., Møller, M. H., Perner, A., Myatra, S. N., Jha, V., Jha, V., Jha, V., Hammond, N., Micallef, S., Venkatesh, B., Hammond, N., Lange, T., Munch, M. W., Myatra, S. N., Tirupakuzhi Vijayaraghavan, B. K., Saseedharan, S., ... the COVID-STEROID 2 collaborators (2024). 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. The Lancet Regional Health - Southeast Asia, 20, [100293]. https://doi.org/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. / Tirupakuzhi Vijayaraghavan, Bharath Kumar; Granholm, Anders; Munch, Marie W.; Kjær, Maj Brit N.; Møller, Morten H.; Perner, Anders; Myatra, Sheila N.; Jha, Vivekanand; Jha, Vivekanand; Jha, Vivekanand; Hammond, Naomi; Micallef, Sharon; Venkatesh, Balasubramanian; Hammond, Naomi; Lange, Theis; Munch, Marie W.; Myatra, Sheila N.; Tirupakuzhi Vijayaraghavan, Bharath Kumar; Saseedharan, Sanjith; Benfield, Thomas; Wahlin, Rebecka R.; Rasmussen, Bodil S.; Andreasen, Anne Sofie; Poulsen, Lone M.; Cioccari, Luca; Khan, Mohd S.; Kapadia, Farhad; Divatia, Jigeeshu V.; Brøchner, Anne C.; Bestle, Morten H.; Helleberg, Marie; Michelsen, Jens; Padmanaban, Ajay; Bose, Neeta; Møller, Anders; Borawake, Kapil; Kristiansen, Klaus T.; Shukla, Urvi; Chew, Michelle S.; Ulrik, Charlotte S.; Kjær, Maj Brit N.; Møller, Morten H.; Meyhoff, Tine S.; Vesterlund, Gitte K.; Gluud, Christian; Lange, Theis ; Marcussen, Klaus V.; Nielsen, Henrik; Jensen, Thomas S.; Perner, Anders; the COVID-STEROID 2 collaborators.

In: The Lancet Regional Health - Southeast Asia, Vol. 20, 100293, 2024.

Research output: Contribution to journal › Journal article › Research › peer-review

Tirupakuzhi Vijayaraghavan, BK, Granholm, A, Munch, MW, Kjær, MBN, Møller, MH , Perner, A, Myatra, SN, Jha, V, Jha, V, Jha, V, Hammond, N, Micallef, S, Venkatesh, B, Hammond, N, Lange, T, Munch, MW, Myatra, SN, Tirupakuzhi Vijayaraghavan, BK, Saseedharan, S, Benfield, T, Wahlin, RR, Rasmussen, BS, Andreasen, AS, Poulsen, LM, Cioccari, L, Khan, MS, Kapadia, F, Divatia, JV, Brøchner, AC, Bestle, MH , Helleberg, M, Michelsen, J, Padmanaban, A, Bose, N, Møller, A, Borawake, K, Kristiansen, KT, Shukla, U, Chew, MS, Ulrik, CS, Kjær, MBN, Møller, MH, Meyhoff, TS, Vesterlund, GK, Gluud, C, Lange, T , Marcussen, KV, Nielsen, H, Jensen, TS, Perner, A & the COVID-STEROID 2 collaborators 2024, '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', The Lancet Regional Health - Southeast Asia, vol. 20, 100293. https://doi.org/10.1016/j.lansea.2023.100293

Tirupakuzhi Vijayaraghavan BK, Granholm A, Munch MW, Kjær MBN, Møller MH , Perner A et al. 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. The Lancet Regional Health - Southeast Asia. 2024;20. 100293. https://doi.org/10.1016/j.lansea.2023.100293

Tirupakuzhi Vijayaraghavan, Bharath Kumar ; Granholm, Anders ; Munch, Marie W. ; Kjær, Maj Brit N. ; Møller, Morten H. ; Perner, Anders ; Myatra, Sheila N. ; Jha, Vivekanand ; Jha, Vivekanand ; Jha, Vivekanand ; Hammond, Naomi ; Micallef, Sharon ; Venkatesh, Balasubramanian ; Hammond, Naomi ; Lange, Theis ; Munch, Marie W. ; Myatra, Sheila N. ; Tirupakuzhi Vijayaraghavan, Bharath Kumar ; Saseedharan, Sanjith ; Benfield, Thomas ; Wahlin, Rebecka R. ; Rasmussen, Bodil S. ; Andreasen, Anne Sofie ; Poulsen, Lone M. ; Cioccari, Luca ; Khan, Mohd S. ; Kapadia, Farhad ; Divatia, Jigeeshu V. ; Brøchner, Anne C. ; Bestle, Morten H. ; Helleberg, Marie ; Michelsen, Jens ; Padmanaban, Ajay ; Bose, Neeta ; Møller, Anders ; Borawake, Kapil ; Kristiansen, Klaus T. ; Shukla, Urvi ; Chew, Michelle S. ; Ulrik, Charlotte S. ; Kjær, Maj Brit N. ; Møller, Morten H. ; Meyhoff, Tine S. ; Vesterlund, Gitte K. ; Gluud, Christian ; Lange, Theis ; Marcussen, Klaus V. ; Nielsen, Henrik ; Jensen, Thomas S. ; Perner, Anders ; the COVID-STEROID 2 collaborators. / 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. In: The Lancet Regional Health - Southeast Asia. 2024 ; Vol. 20.

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title = "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",

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",

author = "{Tirupakuzhi Vijayaraghavan}, {Bharath Kumar} and Anders Granholm and Munch, {Marie W.} and Kj{\ae}r, {Maj Brit N.} and M{\o}ller, {Morten H.} and Anders Perner and Myatra, {Sheila N.} and Vivekanand Jha and Vivekanand Jha and Vivekanand Jha and Naomi Hammond and Sharon Micallef and Balasubramanian Venkatesh and Naomi Hammond and Theis Lange and Munch, {Marie W.} and Myatra, {Sheila N.} and {Tirupakuzhi Vijayaraghavan}, {Bharath Kumar} and Sanjith Saseedharan and Thomas Benfield and Wahlin, {Rebecka R.} and Rasmussen, {Bodil S.} and Andreasen, {Anne Sofie} and Poulsen, {Lone M.} and Luca Cioccari and Khan, {Mohd S.} and Farhad Kapadia and Divatia, {Jigeeshu V.} and Br{\o}chner, {Anne C.} and Bestle, {Morten H.} and Marie Helleberg and Jens Michelsen and Ajay Padmanaban and Neeta Bose and Anders M{\o}ller and Kapil Borawake and Kristiansen, {Klaus T.} and Urvi Shukla and Chew, {Michelle S.} and Ulrik, {Charlotte S.} and Kj{\ae}r, {Maj Brit N.} and M{\o}ller, {Morten H.} and Meyhoff, {Tine S.} and Vesterlund, {Gitte K.} and Christian Gluud and Theis Lange and Marcussen, {Klaus V.} and Henrik Nielsen and Jensen, {Thomas S.} and Anders Perner and {the COVID-STEROID 2 collaborators}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2024",

doi = "10.1016/j.lansea.2023.100293",

language = "English",

volume = "20",

journal = "The Lancet Regional Health - Southeast Asia",

issn = "2772-3682",

publisher = "Elsevier",

}

TY - JOUR

T1 - 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

AU - Tirupakuzhi Vijayaraghavan, Bharath Kumar

AU - Granholm, Anders

AU - Munch, Marie W.

AU - Kjær, Maj Brit N.

AU - Møller, Morten H.

AU - Perner, Anders

AU - Myatra, Sheila N.

AU - Jha, Vivekanand

AU - Hammond, Naomi

AU - Micallef, Sharon

AU - Venkatesh, Balasubramanian

AU - Hammond, Naomi

AU - Lange, Theis

AU - Munch, Marie W.

AU - Myatra, Sheila N.

AU - Tirupakuzhi Vijayaraghavan, Bharath Kumar

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 - Ulrik, Charlotte S.

AU - Kjær, Maj Brit N.

AU - Møller, Morten H.

AU - Meyhoff, Tine S.

AU - Vesterlund, Gitte K.

AU - Gluud, Christian

AU - Lange, Theis

AU - Marcussen, Klaus V.

AU - Nielsen, Henrik

AU - Jensen, Thomas S.

AU - Perner, Anders

AU - the COVID-STEROID 2 collaborators

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - COVID-19

KW - Developing countries

KW - Randomised controlled trials

KW - Steroids

U2 - 10.1016/j.lansea.2023.100293

DO - 10.1016/j.lansea.2023.100293

M3 - Journal article

C2 - 38234702

AN - SCOPUS:85173170884

VL - 20

JO - The Lancet Regional Health - Southeast Asia

JF - The Lancet Regional Health - Southeast Asia

SN - 2772-3682

M1 - 100293

ER -