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; Morten Bestle

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, 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, Morten Bestle (Medlem af forfattergruppering)

^*Corresponding author af dette arbejde

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.

Originalsprog	Engelsk
Artikelnummer	100293
Tidsskrift	The Lancet regional health. Southeast Asia
Vol/bind	20
Sider (fra-til)	1-8
Antal sider	8
ISSN	2772-3682
DOI	https://doi.org/10.1016/j.lansea.2023.100293
Status	Udgivet - jan. 2024

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Tirupakuzhi Vijayaraghavan, B. K., Granholm, A., Myatra, S. N., Jha, V., Hammond, N., Micallef, S., Munch, M. W., Kjær, M.-B. N., Møller, M. H., Lange, T., Perner, A., Venkatesh, B., COVID-STEROID 2 collaborators, & Bestle, M. (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, 1-8. Artikel 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; Myatra, Sheila N et al.
I: The Lancet regional health. Southeast Asia, Bind 20, 100293, 01.2024, s. 1-8.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Tirupakuzhi Vijayaraghavan, BK, Granholm, A, Myatra, SN, Jha, V, Hammond, N, Micallef, S, Munch, MW , Kjær, M-BN , Møller, MH, Lange, T, Perner, A, Venkatesh, B, COVID-STEROID 2 collaborators & Bestle, M 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, bind 20, 100293, s. 1-8. https://doi.org/10.1016/j.lansea.2023.100293

Tirupakuzhi Vijayaraghavan BK, Granholm A, Myatra SN, Jha V, Hammond N, Micallef S 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 jan.;20:1-8. 100293. doi: 10.1016/j.lansea.2023.100293

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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 Myatra, {Sheila N} and Vivekanand Jha and Naomi Hammond and Sharon Micallef and Munch, {Marie Warrer} and Kj{\ae}r, {Maj-Brit N} and M{\o}ller, {Morten Hylander} and Theis Lange and Anders Perner and Balasubramanian Venkatesh and {COVID-STEROID 2 collaborators} and Morten Bestle",

note = "{\textcopyright} 2023 The Author(s).",

year = "2024",

month = jan,

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

language = "English",

volume = "20",

pages = "1--8",

journal = "The Lancet regional health. Southeast Asia",

issn = "2772-3682",

publisher = "Elsevier Ltd",

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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 - Myatra, Sheila N

AU - Jha, Vivekanand

AU - Hammond, Naomi

AU - Micallef, Sharon

AU - Munch, Marie Warrer

AU - Kjær, Maj-Brit N

AU - Møller, Morten Hylander

AU - Lange, Theis

AU - Perner, Anders

AU - Venkatesh, Balasubramanian

AU - COVID-STEROID 2 collaborators

A2 - Bestle, Morten

PY - 2024/1

Y1 - 2024/1

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

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U2 - 10.1016/j.lansea.2023.100293

DO - 10.1016/j.lansea.2023.100293

M3 - Journal article

C2 - 38234702

SN - 2772-3682

VL - 20

SP - 1

EP - 8

JO - The Lancet regional health. Southeast Asia

JF - The Lancet regional health. Southeast Asia

M1 - 100293

ER -

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

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