by Chevret Sylvie,
Bouadma Lila, Dupuis Claire, Burdet Charles and Timsit Jean-François
Annals of
Intensive Care volume 13,
Article number: 75 (2023)
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.
