DECIMAL: Dexamethasone in COVID-19 with Moderate-to-Severe ARDS (2021)

“In patients with moderate to severe ARDS due to COVID-19, dexamethasone treatment was not associated with a significant reduction in the number of ventilator-free days at 28 days.”

  • The DECIMAL Investigators

1. Publication Details

  • Trial Title: Dexamethasone in Patients with COVID-19 and Moderate-to-Severe Acute Respiratory Distress Syndrome: A Multicenter Randomized Clinical Trial
  • Citation: Bouadma L, Mekontso-Dessap A, Burle B, et al. Dexamethasone in Patients with COVID-19 and Moderate-to-Severe Acute Respiratory Distress Syndrome: A Multicenter Randomized Clinical Trial. JAMA Intern Med. 2021;181(6):787-796. DOI: 10.1001/jamainternmed.2021.1377
  • Published: June 1, 2021, in JAMA Internal Medicine
  • Author: Lila Bouadma, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

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

3. The Clinical Question

  • In adult patients with moderate to severe ARDS due to COVID-19 (Population), does treatment with intravenous dexamethasone (Intervention) compared to standard care without corticosteroids (Comparison) increase the number of ventilator-free days at 28 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: At the beginning of the COVID-19 pandemic, the role of corticosteroids was highly uncertain. While they had shown benefit in non-viral ARDS, their use in viral pneumonia was controversial due to concerns about delayed viral clearance.
  • Knowledge Gap: There was an urgent need for high-quality randomized controlled trial evidence to determine if corticosteroids were beneficial or harmful in the sickest patients with COVID-19—those with established moderate to severe ARDS.
  • Proposed Hypothesis: The authors hypothesized that treatment with dexamethasone would be superior to standard care in increasing the number of ventilator-free days in patients with COVID-19-related ARDS.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 17 intensive care units (ICUs) in France and Brazil.
  • Trial Period: Enrollment ran from March to May 2020.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with confirmed COVID-19 and moderate to severe ARDS (PaO2:FiO2 ratio < 200) who had been on mechanical ventilation for less than 48 hours.
    • Exclusion Criteria: Included pregnancy, immunosuppression, and a decision to withhold life-sustaining treatment.
  • Intervention: Patients received intravenous dexamethasone (20 mg once daily for 5 days, then 10 mg once daily for 5 days).
  • Control: Patients received standard care without corticosteroids.
  • Management Common to Both Groups: All patients received standard supportive care for COVID-19 ARDS, which could include antiviral therapy and other immunomodulators.
  • Power and Sample Size: The authors calculated that a sample size of 300 patients would be required to have 80% power to detect a 4-day difference in ventilator-free days. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: The number of ventilator-free days at 28 days.
    • Secondary Outcomes: Included 60-day mortality and the incidence of secondary infections.

6. Key Results

  • Enrollment and Baseline: 149 patients were randomized (77 to dexamethasone and 72 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board for slow enrollment and after the publication of the RECOVERY trial, which established dexamethasone as the standard of care.
  • Primary Outcome: There was no significant difference in the primary outcome. The median number of ventilator-free days was 3 in the dexamethasone group and 0 in the control group (p=0.07).
  • Secondary Outcomes: 60-day mortality was significantly lower in the dexamethasone group: 19 of 76 patients (25%) died, compared with 26 of 71 patients (37%) in the control group (p=0.04).
  • Adverse Events: The incidence of secondary infections 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 Wilcoxon rank-sum test. Mortality was analyzed with a log-rank test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the median number of ventilator-free days between the two groups.
  • Key Statistic(s) Reported: The key statistics were the median values for the primary outcome and the associated P-value, and the hazard ratio for mortality.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.07 for the primary outcome is above the 0.05 threshold, indicating the result was not statistically significant. The p-value of 0.04 for the secondary outcome of 60-day mortality was statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for the secondary outcome of mortality):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 37% – 25% = 12%.
      • Clinical Meaning: For every 100 patients treated with dexamethasone, about 12 additional deaths were prevented at 60 days.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.12 = 8.3, which is rounded down to 8.
      • Clinical Meaning: You would need to treat 8 patients with this dexamethasone regimen to prevent one additional death.
  • Subgroup Analyses: Not reported due to the small sample size.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided important early evidence during the pandemic.
  • Patient-Centered Outcomes: The study included the crucial patient-centered outcome of mortality.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are specific to the high-dose dexamethasone regimen used in this trial.
  • Other: The trial was severely underpowered. It was stopped after enrolling only 149 of the planned 300 patients, which makes it impossible to draw any definitive conclusions from its findings. The positive mortality result is a secondary outcome from an underpowered trial and should be considered hypothesis-generating only.

10. Conclusion of the Authors

  • The authors concluded that in patients with COVID-19 and moderate-to-severe ARDS, treatment with dexamethasone was not associated with a significant increase in ventilator-free days, but was associated with a reduction in 60-day mortality.

11. To Summarize

  • Impact on Current Practice: This trial was one of several early corticosteroid trials in COVID-19. Its findings, particularly the mortality signal, were consistent with and supportive of the larger, definitive RECOVERY trial, which established the role of dexamethasone.
  • Specific Recommendations:
    • Patient Selection: For adult patients with moderate to severe COVID-19 ARDS.
    • Actionable Intervention: The results support the use of corticosteroids in this population.
  • What This Trial Does NOT Mean: This trial does NOT definitively prove a mortality benefit on its own due to its small size and early termination.
  • Implementation Caveats: The evidence from the larger RECOVERY trial is the primary driver for the use of dexamethasone in severe COVID-19.

12. Context and Related Studies

  • Building on Previous Evidence: The DECIMAL trial (2021) was designed in the early days of the pandemic to test the corticosteroid hypothesis in severe COVID-19.
  • Influence on Subsequent Research: The trial was largely superseded by the massive RECOVERY trial (2020), whose definitive positive result for dexamethasone made it ethically challenging to continue randomizing patients to a no-steroid arm, leading to the early termination of DECIMAL and other similar trials.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal dose and duration of corticosteroid therapy in different phenotypes of COVID-19 ARDS remain areas of investigation.
  • Future Directions: Research has largely shifted to focus on other immunomodulatory therapies and the management of long-term complications of COVID-19.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a critical therapeutic question at the height of the COVID-19 pandemic.
  • Methods: The multicenter RCT design was appropriate. The main methodological limitations are the open-label design and, most importantly, the severe underpowering due to early termination, which makes the results inconclusive.
  • Results: The study was negative for its primary outcome. The statistically significant finding for the secondary outcome of mortality is intriguing but must be interpreted with extreme caution, as it is a secondary outcome from an underpowered trial and has a high risk of being a false-positive result.
  • Conclusions and Applicability: The authors’ cautious conclusion is appropriate. The trial’s main contribution is as a piece of the larger puzzle of corticosteroid evidence in COVID-19. Its findings are consistent with and supportive of the larger, more definitive RECOVERY trial.

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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