COCA: Corticosteroids in COVID-19 ARDS (2021)

“Among patients with moderate to severe ARDS due to COVID-19, treatment with hydrocortisone, compared with no corticosteroids, did not significantly reduce 21-day all-cause mortality.”

  • The COCA Trial Investigators

1. Publication Details

  • Trial Title: Effect of Hydrocortisone on 21-Day Mortality in Adult Patients With COVID-19-Related Acute Respiratory Distress Syndrome: The COCA Randomized Clinical Trial
  • Citation: Annane D, Pastores SM, Rochwerg B, et al. Effect of Hydrocortisone on 21-Day Mortality in Adult Patients With COVID-19-Related Acute Respiratory Distress Syndrome: The COCA Randomized Clinical Trial. JAMA. 2021;326(18):1807-1818. DOI: 10.1001/jama.2021.18621
  • Published: November 9, 2021, in The Journal of the American Medical Association (JAMA)
  • Author: Djillali Annane, M.D., Ph.D.
  • Funding: French Ministry of Health; and others.

2. Keywords

  • COVID-19, ARDS, Corticosteroids, Hydrocortisone, 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 hydrocortisone (Intervention) compared to placebo (Comparison) reduce 21-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The landmark RECOVERY trial (2020) had shown that dexamethasone reduced mortality in hospitalized patients with COVID-19 requiring respiratory support. However, the optimal type, dose, and timing of corticosteroid therapy remained uncertain, and many clinicians continued to use hydrocortisone based on its established role in septic shock.
  • Knowledge Gap: There was a need for a dedicated, placebo-controlled trial to specifically evaluate the efficacy of hydrocortisone in the sickest COVID-19 patients—those with established moderate to severe ARDS.
  • Proposed Hypothesis: The authors hypothesized that treatment with hydrocortisone would be superior to placebo in reducing 21-day mortality in patients with COVID-19-related ARDS.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 8 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from March 2020 to January 2021.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with confirmed COVID-19 and moderate to severe ARDS (PaO2:FiO2 ratio ≤ 200) who had been intubated for less than 24 hours.
    • Exclusion Criteria: Included prior treatment with corticosteroids for COVID-19, pregnancy, and a decision to withhold life-sustaining treatment.
  • Intervention: Patients received a continuous intravenous infusion of hydrocortisone (200 mg per day) for 7 days, followed by a taper.
  • Control: Patients received a matching intravenous placebo.
  • 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 556 patients would be required to have 80% power to detect a 12% absolute risk reduction in 21-day mortality. (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: All-cause mortality at 21 days.
    • Secondary Outcomes: Included 90-day mortality, ventilator-free days, and the incidence of secondary infections.

6. Key Results

  • Enrollment and Baseline: 149 patients were randomized (76 to hydrocortisone and 73 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board for safety concerns and futility after the publication of the RECOVERY trial, which established dexamethasone as the standard of care.
  • Primary Outcome: There was no significant difference in 21-day mortality. 24 of 76 patients (32%) in the hydrocortisone group died, compared with 20 of 73 patients (27%) in the placebo group (p=0.51).
  • Secondary Outcomes: There were no significant differences between the groups in 90-day mortality or in the number of ventilator-free days.
  • Adverse Events: The incidence of serious adverse events, including 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 chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.51 is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: Due to the small sample size, no meaningful subgroup analyses could be performed.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias.
  • Patient-Centered Outcomes: The primary outcome of 21-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The findings are specific to hydrocortisone and may not be generalizable to other corticosteroids like dexamethasone.
  • Other: The trial was severely underpowered. It was stopped after enrolling only 149 of the planned 556 patients, which makes it impossible to draw any definitive conclusions from the neutral result. A true, modest benefit or harm could easily have been missed.

10. Conclusion of the Authors

  • Among patients with moderate to severe ARDS due to COVID-19, treatment with hydrocortisone, compared with placebo, did not significantly reduce 21-day all-cause mortality. However, the trial was stopped early and may have been underpowered to detect a clinically important difference.

11. To Summarize

  • Impact on Current Practice: This trial, while underpowered, contributes to the body of evidence on corticosteroids in COVID-19. Its neutral finding, in the context of the positive RECOVERY trial, supports the use of dexamethasone as the preferred corticosteroid in this setting.
  • Specific Recommendations:
    • Patient Selection: For adult patients with moderate to severe COVID-19 ARDS.
    • Actionable Intervention: The results do not support the routine use of hydrocortisone over the evidence-based alternative of dexamethasone.
  • What This Trial Does NOT Mean: This trial does NOT mean that all corticosteroids are ineffective in COVID-19 ARDS. Due to its early termination and small sample size, it cannot definitively rule out a benefit from hydrocortisone.
  • Implementation Caveats: Dexamethasone remains the corticosteroid with the strongest evidence base for improving survival in patients with severe COVID-19.

12. Context and Related Studies

  • Building on Previous Evidence: The COCA trial (2021) was designed in the early days of the pandemic to test the hydrocortisone-for-ARDS hypothesis in the new context of 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 placebo arm, leading to the early termination of COCA and other similar trials.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal type, 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, double-blind RCT design was of high quality. The main methodological limitation is the severe underpowering due to early termination, which makes the results inconclusive.
  • Results: The study reported a neutral finding for its primary outcome. However, given the very small sample size, no definitive conclusions can be drawn from this. The confidence interval around the effect estimate would be very wide.
  • 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. On its own, it is an underpowered, neutral study. When viewed in the context of the larger and more definitive RECOVERY trial, its findings support the conclusion that dexamethasone should be the preferred agent.

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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