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 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 ).

Keywords: ARDS; Acute respiratory failure; Bayesian analysis; Critical care; Dose; Interaction; Remdesivir; SARS-Cov-2; Sepsis; Steroids.

Fig. 1

COVIDICUS Trial: Main trial outcome across the DXM randomized groups. Overall survival according to randomization (a) and posterior density of the hazard ratio (HR) of the 60-day mortality rate in the whole trial population based on a noninformative prior (b) or using either a sceptical or an enthusiastic prior (c)

Fig. 2

Looking for treatment by subset interactions in terms of hazard ratio (HR) of 60-day mortality. CRP C reactive protein, MV invasive mechanical ventilation, SAPS Simplified Acute Physiology Score

Fig. 3

Posterior density of the hazard ratio of death within 60 deaths in DXM20 over DXMSoc group, according to subsets. Subsets were defined by age (< , > 70, Fig. 2a), by time since symptoms onset (< , > 7 days, Fig. 2b) and by remdesivir use or not (Fig. 2c)