Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial
Abstract Background The respective benefits of high and low doses of dexamethasone (DXM) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and acute respiratory failure (ARF) are controversial, with two large triple-blind RCTs reaching very important difference in the effe...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2023-08-01
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| Series: | Annals of Intensive Care |
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| Online Access: | https://doi.org/10.1186/s13613-023-01168-z |
| _version_ | 1797451498425155584 |
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| author | Sylvie Chevret Lila Bouadma Claire Dupuis Charles Burdet Jean-François Timsit the COVIDICUS RCT group |
| author_facet | Sylvie Chevret Lila Bouadma Claire Dupuis Charles Burdet Jean-François Timsit the COVIDICUS RCT group |
| author_sort | Sylvie Chevret |
| collection | DOAJ |
| description | Abstract Background The respective benefits of high and low doses of dexamethasone (DXM) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and acute respiratory failure (ARF) are controversial, with two large triple-blind RCTs reaching very important difference in the effect-size. In the COVIDICUS trial, no evidence of additional benefit of high-dose dexamethasone (DXM20) was found. We aimed to explore whether some specific patient phenotypes could benefit from DXM20 compared to the standard of care 6 mg dose of DXM (DXMSoC). Methods We performed a post hoc exploratory Bayesian analysis of 473 patients who received either DXMSoc or DXM20 in the COVIDICUS trial. The outcome was the 60 day mortality rate of DXM20 over DXMSoC, with treatment effect measured on the hazard ratio (HR) estimated from Cox model. Bayesian analyses allowed to compute the posterior probability of a more than trivial benefit (HR < 0.95), and that of a potential harm (HR > 1.05). Bayesian measures of interaction then quantified the probability of interaction (Pr Interact) that the HR of death differed across the subsets by 20%. Primary analyses used noninformative priors, centred on HR = 1.00. Sensitivity analyses used sceptical and enthusiastic priors, based on null (HR = 1.00) or benefit (HR = 0.95) effects. Results Overall, the posterior probability of a more than trivial benefit and potential harm was 29.0 and 51.1%, respectively. There was some evidence of treatment by subset interaction (i) according to age (Pr Interact, 84%), with a 86.5% probability of benefit in patients aged below 70 compared to 22% in those aged above 70; (ii) according to the time since symptoms onset (Pr Interact, 99%), with a 99.9% probability of a more than trivial benefit when lower than 7 days compared to a < 0.1% probability when delayed by 7 days or more; and (iii) according to use of remdesivir (Pr Interact, 91%), with a 90.1% probability of benefit in patients receiving remdesivir compared to 19.1% in those who did not. Conclusions In this exploratory post hoc Bayesian analysis, compared with standard-of-care DXM, high-dose DXM may benefit patients aged less than 70 years with severe ARF that occurred less than 7 days after symptoms onset. The use of remdesivir may also favour the benefit of DXM20. Further analysis is needed to confirm these findings. Trial registration: NCT04344730, date of registration April 14, 2020 ( https://clinicaltrials.gov/ct2/show/NCT04344730?term=NCT04344730&draw=2&rank=1 ); EudraCT: 2020-001457-43 ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-001457-43 ). |
| first_indexed | 2024-03-09T14:55:31Z |
| format | Article |
| id | doaj.art-bbbd7ead4c46438f92e2dd3d9fc302ee |
| institution | Directory Open Access Journal |
| issn | 2110-5820 |
| language | English |
| last_indexed | 2024-03-09T14:55:31Z |
| publishDate | 2023-08-01 |
| publisher | SpringerOpen |
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| series | Annals of Intensive Care |
| spelling | doaj.art-bbbd7ead4c46438f92e2dd3d9fc302ee2023-11-26T14:13:17ZengSpringerOpenAnnals of Intensive Care2110-58202023-08-0113111210.1186/s13613-023-01168-zWhich severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trialSylvie Chevret0Lila Bouadma1Claire Dupuis2Charles Burdet3Jean-François Timsit4the COVIDICUS RCT groupECSTRRA, UMR 1153, Saint Louis Hospital, University Paris CitéMedical and Infectious Diseases ICU, APHP Bichat HospitalUniversité Paris Cité, IAME, INSERM, UMR 1137Université Paris Cité, IAME, INSERM, UMR 1137Medical and Infectious Diseases ICU, APHP Bichat HospitalAbstract Background The respective benefits of high and low doses of dexamethasone (DXM) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and acute respiratory failure (ARF) are controversial, with two large triple-blind RCTs reaching very important difference in the effect-size. In the COVIDICUS trial, no evidence of additional benefit of high-dose dexamethasone (DXM20) was found. We aimed to explore whether some specific patient phenotypes could benefit from DXM20 compared to the standard of care 6 mg dose of DXM (DXMSoC). Methods We performed a post hoc exploratory Bayesian analysis of 473 patients who received either DXMSoc or DXM20 in the COVIDICUS trial. The outcome was the 60 day mortality rate of DXM20 over DXMSoC, with treatment effect measured on the hazard ratio (HR) estimated from Cox model. Bayesian analyses allowed to compute the posterior probability of a more than trivial benefit (HR < 0.95), and that of a potential harm (HR > 1.05). Bayesian measures of interaction then quantified the probability of interaction (Pr Interact) that the HR of death differed across the subsets by 20%. Primary analyses used noninformative priors, centred on HR = 1.00. Sensitivity analyses used sceptical and enthusiastic priors, based on null (HR = 1.00) or benefit (HR = 0.95) effects. Results Overall, the posterior probability of a more than trivial benefit and potential harm was 29.0 and 51.1%, respectively. There was some evidence of treatment by subset interaction (i) according to age (Pr Interact, 84%), with a 86.5% probability of benefit in patients aged below 70 compared to 22% in those aged above 70; (ii) according to the time since symptoms onset (Pr Interact, 99%), with a 99.9% probability of a more than trivial benefit when lower than 7 days compared to a < 0.1% probability when delayed by 7 days or more; and (iii) according to use of remdesivir (Pr Interact, 91%), with a 90.1% probability of benefit in patients receiving remdesivir compared to 19.1% in those who did not. Conclusions In this exploratory post hoc Bayesian analysis, compared with standard-of-care DXM, high-dose DXM may benefit patients aged less than 70 years with severe ARF that occurred less than 7 days after symptoms onset. The use of remdesivir may also favour the benefit of DXM20. Further analysis is needed to confirm these findings. Trial registration: NCT04344730, date of registration April 14, 2020 ( https://clinicaltrials.gov/ct2/show/NCT04344730?term=NCT04344730&draw=2&rank=1 ); EudraCT: 2020-001457-43 ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-001457-43 ).https://doi.org/10.1186/s13613-023-01168-zSARS-Cov-2SteroidsDoseSepsisAcute respiratory failureRemdesivir |
| spellingShingle | Sylvie Chevret Lila Bouadma Claire Dupuis Charles Burdet Jean-François Timsit the COVIDICUS RCT group Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial Annals of Intensive Care SARS-Cov-2 Steroids Dose Sepsis Acute respiratory failure Remdesivir |
| title | Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial |
| title_full | Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial |
| title_fullStr | Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial |
| title_full_unstemmed | Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial |
| title_short | Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial |
| title_sort | which severe covid 19 patients could benefit from high dose dexamethasone a bayesian post hoc reanalysis of the covidicus randomized clinical trial |
| topic | SARS-Cov-2 Steroids Dose Sepsis Acute respiratory failure Remdesivir |
| url | https://doi.org/10.1186/s13613-023-01168-z |
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