Long-term outcomes of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia

Abstract

Purpose: We assessed long-term outcomes of dexamethasone 12 mg versus 6 mg given daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia.

Methods: We assessed 180-day mortality and health-related quality of life (HRQoL) using EuroQoL (EQ)-5D-5L index values and EQ visual analogue scale (VAS) in the international, stratified, blinded COVID STEROID 2 trial, which randomised 1000 adults with confirmed COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India. In the HRQoL analyses, higher values indicated better outcomes, and deceased patients were given a score of zero.

Results: We obtained vital status at 180 days for 963 of 982 patients (98.1%) in the intention-to-treat population, EQ-5D-5L index value data for 922 (93.9%) and EQ VAS data for 924 (94.1%). At 180 days, 164 of 486 patients (33.7%) had died in the 12 mg group versus 184 of 477 (38.6%) in the 6 mg group [adjusted risk difference - 4.3%; 99% confidence interval (CI) - 11.7-3.0; relative risk 0.89; 0.72-1.09; P = 0.13]. The adjusted mean differences between the 12 mg and the 6 mg groups in EQ-5D-5L index values were 0.06 (99% CI - 0.01 to 0.12; P = 0.10) and in EQ VAS scores 4 (- 3 to 10; P = 0.22).

Conclusion: Among patients with COVID-19 and severe hypoxaemia, dexamethasone 12 mg compared with 6 mg did not result in statistically significant improvements in mortality or HRQoL at 180 days, but the results were most compatible with benefit from the higher dose.

Trial registration: ClinicalTrials.gov NCT04509973.

Keywords: COVID-19; Corticosteroids; Critical illness; Hypoxaemia; Mortality; Quality of life.

Conflict of interest statement

AG, MBNK, MWM, GKV, TSM, MHM and AP are affiliated with the Dept. of Intensive Care, Rigshospitalet, which has received grants for research from Pfizer, Fresenius Kabi, AM Pharma, and Sygeforsikringen ‘danmark’ outside the submitted work. MH has participated in advisory boards for AstraZeneca, GSK, Gilead, MSD, Roche and Sobi and received speaker’s honoraria from GSK and Gilead. TB reports grants from Novo Nordisk Foundation, grants from Simonsen Foundation, grants and personal fees from GSK, grants and personal fees from Pfizer, personal fees from Astra Zeneca, personal fees from Janssen, personal fees from Boehringer Ingelheim, grants and personal fees from Gilead, personal fees from MSD, grants from Lundbeck Foundation, grants from Kai Hansen Foundation, personal fees from Pentabase ApS, grants from Erik and Susanna Olesen’s Charitable Fund, outside the submitted work. SMJ and LC are affiliated with Inselspital, Bern University Hospital, which has received grants from Edwards Lifesciences Services GmbH, Phagenesis Limited, and Nestlé outside the submitted work. JVD has received personal fees (paid to his institution) from Edwards India outside the submitted work. VJ has received grant funding from GSK, Baxter Healthcare, and Biocon and honoraria from Boehringer Ingelheim, Astra Zeneca, Baxter Healthcare, Bayer, NephroPlus and Zydus Cadilla, under the policy of all monies being paid to the organization.

© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.

Figures

Fig. 1

Patient flow in the COVID STEROID 2 trial. The details up to 90 days were presented in the primary report [4]. Eighteen patients withdrew consent for the use of any data (12 patients before the first dosing of trial medication and 6 after); the intention-to-treat (ITT) population therefore consisted of 982 patients in total. There were patient withdraws at three levels because of repeated follow-up of patients. *The primary HRQoL analyses were done in the ITT population (n = 982) with deceased patients assigned zero and missing data (n = 60 for EQ-5D-5L index values and n = 58 for EQ VAS scores) multiply imputed

Fig. 2

Time to death or censoring and distribution of HRQoL data at 180 days in the two intervention groups. A Mortality curves in the two intervention groups up to 180 days. Patients who withdrew consent for further data registration or were lost to follow-up were censored at the time of the withdrawal or loss to follow-up. The time to death was compared post hoc using Cox regression with results presented as an unadjusted hazard ratio (HR) with 99% confidence interval (CI) and P value. B Distribution of the HRQoL data as horizontally stacked proportions in the two intervention groups. Patients who died within 180 days after randomisation were assigned the value 0, corresponding to a health state equal to being dead for EQ-5D-5L index values and the worst possible value for EQ VAS. Data from non-respondents were multiply imputed (n = 60 for the index values and n = 58 for EQ VAS scores). Red represents worse outcomes, and blue represents better outcomes. For EQ-5D-5L index values, < 1% of the values in each group in the imputed datasets were below 0, corresponding to health states worse than being dead. These values are displayed together with the value zero

Fig. 3

Distribution of single HRQoL domain levels among the 180-day survivors in the two intervention groups. Values are from the responding survivors only (patients (n = 503) and relatives on behalf of patients (n = 73; for these 73 patients, relatives were unable to respond for one patient in the 12 mg group in the usual activities domain and for one patient in the 12 mg group in the anxiety/depression domain)). Patients or relatives answered one of 5 levels (no problems or slight, moderate, severe, or extreme problems) for each of the 5 domains in the EQ-5D-5L survey. The corresponding numeric data are presented in Table S2, ESM 3