COVID STEROID 2

Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxia: an international, randomized, blinded trial

Much. medRxiv Preprint 2021 doi: https://doi.org/10.1101/2021.07.22.21260755

Clinical Question

  • In patients with severe COVID, does 12mg dexamethasone vs 6mg dexamethasone increase the number of days alive without life support at 28 days?

Background

  • The Recovery trial demonstrated a mortality benefit with the use of 6mg dexamethasone in patients with COVID-19
  • A meta-analysis of 7 trials of patients who were critically ill with COVID-19 found a mortality benefit with the use of steroids. The trials included used a dexamethasone equivalent dose of 6-16mg. However, the majority of patients included were from the RECOVERY trial
  • In a non-COVID ARDS trial (DEXA-ARDS) the use of higher dose dexamethasone (20mg from day 1-5, then 10mg from day 6-10) compared with standard treatment resulted in significantly fewer ventilator days
  • There are concerns about the side effects with higher doses of steroids, particularly severe fungal infections
  • This trial tried to determine if patients who had severe COVID-19, would benefit from a higher dose of dexamethasone

Design

  • Randomised controlled trial
    • Computer generated allocation sequence
    • Stratified by trial site, age below 70 years, and use of mechanical ventilation at time of screening
    • Permuted blocks of varying size
  • Blinding of patients, clinicians and trial investigators/statisticians
  • Sample size calculation: 1000 patients required for trial to have a 85% power to show a relative reduction of 15% in 28 day mortality and a 10% reduction in time on life support from a baseline of 30% mortality and 10% remaining on life support at day 28
  • Intention to treat analysis (included 8 patients who were erroneously randomised but not patients who did not consent to the use of their data)
  • Primary outcome assessed using the Kryger Jensen and Lange test adjusted for stratification variables
  • Registered on clinicaltrials.gov

Setting

  • 31 sites between 26 hospitals in Europe and India
    • 485 patients in Denmark, 369 in India, 79 in Sweden, 49 in Switzerland
  • Data collected: August 2020 – May 2021

Population

  • Inclusion:
    • Adult patients hospitalised with confirmed COVID-19
    • Use of either
      • Supplemental oxygen at a flow of at least 10l/min (mask or nasal cannula)
      • Non-invasive ventilation or CPAP
      • Invasive mechanical ventilation
  • Exclusion:
    • Used systemic corticosteroids for other indications in doses higher than 6mg dexamethasone equivalents
    • Had used systemic corticosteroids for COVID-19 for 5 days or more
    • Invasive fungal infections or active TB
    • Pregnancy
    • Hypersensitivity to dexamethasone
    • Informed consent unavailable
  • 1000 patients randomised, 982 patients included in intention to treat population, and 971 patients had data for the primary outcome analysis
  • Comparing baseline characteristics of intervention vs. control group
    • Age: 65 vs 64
    • Male: 70% vs 68%
    • Co-existing conditions
      • Diabetes: 27% vs 34%
      • Immunosuppression therapy within prior 3 months: 8% vs 9%
      • Chronic use of corticosteroids: 3% vs 3%
    • Time from hospitalisation to randomisation: 2 vs 2 days
    • Oxygen supplementation
      • Invasive ventilation
        • 22% vs 20%
        • FiO2: 0.6 vs 0.6
      • Non-invasive ventilation or CPAP
        • 24% vs 26%
        • FiO2: 0.58 vs 0.60
      • Open system
        • 55% vs 53%
        • O2 flow: 22 vs 24l/min
    • Co-interventions used at randomisation
      • Dexamethasone: 1 vs 1 day
      • Vasopressors or inotropes: 16% vs 14%
      • IL-6 inhibitors: 11% vs 10%
      • Use of systemic anti-bacterial agents: 63% vs 66%

Intervention

  • High dose dexamethasone
    • 12mg (as dexamethasone phosphate 14.4mg)

Control

  • Standard dose dexamethasone
    • 6mg (as dexamethasone phosphate 7.2mg)

Management common to both groups

  • Dexamethasone given IV once daily for up to 10 days from randomisation. If patients had used dexamethasone for COVID-19 prior to enrolment, the intervention period was reduced so that patients received dexamethasone fro a maximum of 10 days
    • Given for median 7 vs 6 days
  • Recommended against the use of other immunosuppressive drugs
  • From Jan 2021 the use of tociluzimab was accepted

Outcome

  • Primary outcome: Number of days alive without life support (i.e. invasive mechanical ventilation, circulatory support or renal replacement therapy) at 28 days – no significant difference
    • 22 days (IQR 6-28) vs 20.5 days (4-28), adjusted mean difference 1.3; 95% CI 0.0-2.6, P=0.066
  • Secondary outcomes:
  • Comparing intervention vs. control group
    • No significant difference in
      • 28 day mortality
        • 27.1% vs 32.3%, adjusted relative risk 0.86; 95% CI 0.68-1.08, p=0.097
        • If 3 fewer people had died in the intervention group the result would then have been significantly different (Fisher’s exact test)
      • Serious adverse reactions at 28 days (i.e. new episodes of septic shock, invasive fungal infection, clinically important gastrointestinal bleeding, or anaphylactic reaction to dexamethasone)
        • 11.3% vs 13.2%
  • Post-hoc analysis
    • ECMO used significantly less in intervention group
      • 0.6% vs 2.9%

Authors’ Conclusions

  • Treatment with dexamethasone 12mg vs 6mg did not significantly improve days alive without life support at 28 days , however the lower limit of the 95% CI was 0.0 suggesting that the results are most compatible with a benefit from 12mg

Strengths

  • Randomised controlled trial
  • Blinding of patients, staff and researchers
  • Relatively large sample size
  • Minimal loss to follow up with vast majority of patients receiving treatment that they were allocated to
  • Multi-centre

Weaknesses

  • 29 fewer patients included in primary analysis than planned according to power calculation
  • It may have been preferable to have 28 day mortality as primary outcome
  • We are told the number of patients who received IL-6 inhibitors at randomisation but not the total number that received them during the intervention period

The Bottom Line

  • In patients with severe COVID-19 who were predominately not treated with tociluzimab, the use of 12mg compared with 6mg dexamethasone resulted in no significant difference in the number of days alive without life support at day 28, or 28 day mortality
  • The confidence intervals suggest the potential that there may be a benefit with higher dose dexamethasone but the trial was under-powered to determine this. If there is a difference between treatment groups, it is much less likely that 6mg would give a benefit compared with 12mg. As there was no significant difference in side effects between treatment groups it could be argued that we should change to 12mg dosing for dexamethasone
  • However there were low numbers of patients treated with tociluzimab in this trial. Following the Recovery and REMAP-CAP trial results tociluzimab has become standard care. We do not know the impact that the standard use of tociluzimab would have had on these results
  • I will consider using a higher dose of dexamethasone in patients with severe COVID-19 that are unable to receive tociluzimab. In patients that have received tociluzimab, I will continue to use 6mg of dexamethasone, but in selected cases I would consider escalating this dose
  • An upcoming Bayesian analysis of the data from the study group will hopefully aid the decision making

External Links

Metadata

Summary author: David Slessor
Summary date: 22nd August 2021
Peer-review editor: Segun Olusanya

Image by Sam Moqadam on Unsplash

 

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