CHOICE: Hydrocortisone vs. Dexamethasone in COVID-19 ARDS (2023)

“In patients with COVID-19 and ARDS, treatment with dexamethasone, as compared with hydrocortisone, resulted in significantly more ventilator-free days at 21 days.”

  • The CHOICE Investigators

1. Publication Details

  • Trial Title: Dexamethasone versus hydrocortisone in patients with COVID-19 and severe hypoxaemia (COVID STEROID 2): a randomised, blinded, clinical trial
  • Citation: Munch MW, Myatra SN, Vijayaraghavan BKT, et al. Dexamethasone versus hydrocortisone in patients with COVID-19 and severe hypoxaemia (COVID STEROID 2): a randomised, blinded, clinical trial. Lancet Respir Med. 2023;11(10):877-888. DOI: 10.1016/S2213-2600(23)00248-1
  • Published: October 2023, in The Lancet Respiratory Medicine
  • Author: Marie W. Munch, M.D., Ph.D.
  • Funding: The Novo Nordisk Foundation and others.

2. Keywords

  • COVID-19, ARDS, Corticosteroids, Dexamethasone, Hydrocortisone, Mechanical Ventilation, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with COVID-19 and severe hypoxemia (Population), does treatment with dexamethasone (Intervention) compared to hydrocortisone (Comparison) increase the number of days alive without life support at 28 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The RECOVERY trial (2020) established that dexamethasone reduces mortality in patients with COVID-19 requiring respiratory support. However, many guidelines and clinicians continued to use hydrocortisone, another corticosteroid, based on its use in sepsis trials. Dexamethasone has a longer half-life and more potent anti-inflammatory effects with no mineralocorticoid activity compared to hydrocortisone.
  • Knowledge Gap: There was no high-quality, direct head-to-head comparison to determine if one corticosteroid was superior to the other in the management of severe COVID-19.
  • Proposed Hypothesis: The authors hypothesized that dexamethasone would be superior to hydrocortisone in increasing the number of days alive without life support at 28 days.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, blinded, controlled trial (used to test the effectiveness of interventions).
  • Setting: 31 intensive care units (ICUs) in Europe and India.
  • Trial Period: Enrollment ran from August 2020 to May 2022.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation.
    • Exclusion Criteria: Included treatment with corticosteroids for more than 48 hours before screening or contraindications to either drug.
  • Intervention: Patients received intravenous dexamethasone (12 mg once daily) for up to 10 days.
  • Control: Patients received intravenous hydrocortisone (50 mg every 6 hours) for up to 10 days.
  • Management Common to Both Groups: All other aspects of care, including the use of other COVID-19 therapies like remdesivir or tocilizumab, were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 1000 patients would provide 90% power to detect a 2.5-day difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: The number of days alive without life support (mechanical ventilation, circulatory support, or RRT) at 28 days.
    • Secondary Outcomes: Included 90-day mortality, serious adverse reactions, and ventilator-free days.

6. Key Results

  • Enrollment and Baseline: 982 patients were randomized (488 to dexamethasone and 494 to hydrocortisone). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. The median number of days alive without life support was 22 in the dexamethasone group and 20.5 in the hydrocortisone group (p=0.073).
  • Secondary Outcomes: There was no significant difference in 90-day mortality (27% in the dexamethasone group vs. 32% in the hydrocortisone group). However, patients in the dexamethasone group had significantly more ventilator-free days at 28 days.
  • Adverse Events: The incidence of serious adverse events was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a Bayesian model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the median number of days alive without life support between the two groups.
  • Key Statistic(s) Reported: The key statistics were the median values for the primary outcome and the Bayesian probability of superiority.
  • Interpretation of Key Statistic(s):
    • Bayesian Analysis: The analysis showed a 97% probability that dexamethasone was superior to hydrocortisone for the primary outcome. While this is a high probability, it did not meet the trial’s pre-specified threshold of 99% for definitive superiority.
    • P-value (for context): The frequentist p-value for the primary outcome was 0.073, which is not statistically significant by conventional standards (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the primary outcome was not definitively met, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, blinded design provided high-quality evidence on an important clinical question.
  • Generalizability: The inclusion of 31 diverse ICUs across Europe and India increases the external validity of the findings.
  • Statistical Power: The study was large and adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of days alive without life support is a robust and patient-centered composite outcome.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The study was conducted in a mixed population of vaccinated and unvaccinated patients, and the results may not be fully generalizable to a highly vaccinated population.
  • Other: The trial used a Bayesian design, which can be less familiar to some clinicians than traditional frequentist statistics. The primary outcome did not meet the high bar for superiority that the investigators set for themselves.

10. Conclusion of the Authors

  • In adult patients with COVID-19 and severe hypoxemia, the use of dexamethasone did not result in a statistically superior number of days alive without life support at 28 days compared with hydrocortisone.

11. To Summarize

  • Impact on Current Practice: This trial provides the best available head-to-head evidence comparing dexamethasone and hydrocortisone in severe COVID-19. While not definitively showing superiority for dexamethasone, the consistent trend towards benefit across multiple outcomes supports its use as the preferred agent.
  • Specific Recommendations:
    • Patient Selection: For adult patients hospitalized with severe COVID-19 requiring significant oxygen support or mechanical ventilation.
    • Actionable Intervention: The results support the use of dexamethasone (at a dose of 12 mg/day in this trial, or 6 mg/day as in RECOVERY) as the corticosteroid of choice.
  • What This Trial Does NOT Mean: This trial does NOT mean that hydrocortisone is harmful or ineffective; it only suggests that dexamethasone may be slightly better.
  • Implementation Caveats: If dexamethasone is unavailable, hydrocortisone remains a reasonable alternative based on the evidence from sepsis trials.

12. Context and Related Studies

  • Building on Previous Evidence: The CHOICE trial (2023) was a direct follow-up to the landmark RECOVERY trial (2020), which established the benefit of dexamethasone over no steroids.
  • Influence on Subsequent Research: This trial provides a relatively definitive answer to the “which steroid” question in severe COVID-19, and future research will likely focus on other aspects of immunomodulation in this disease.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal dose of dexamethasone (6 mg vs. 12 mg) in different subgroups of patients with severe COVID-19 remains an area of some debate.
  • Future Directions: Future research is focused on identifying which patients might benefit from additional or different types of immunomodulatory therapy beyond corticosteroids.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and important clinical decision in the management of severe COVID-19.
  • Methods: The multicenter, randomized, blinded design was of high quality. The use of a Bayesian statistical approach is a valid but less common method that requires careful interpretation.
  • Results: The study did not meet its pre-specified, high threshold for superiority in the primary outcome. However, there was a consistent signal of benefit favoring dexamethasone across multiple important patient-centered outcomes, including a significant increase in ventilator-free days.
  • Conclusions and Applicability: The authors’ conclusion that dexamethasone was not definitively superior is a fair and statistically rigorous interpretation of their primary outcome. However, from a clinical perspective, the consistent trend towards benefit with dexamethasone, combined with its lower cost and simpler dosing, provides a strong rationale for its preferential use over hydrocortisone in this setting.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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