RECOVERY: Dexamethasone in Hospitalized Patients with Covid-19 (2020)

“In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.”

  • The RECOVERY Collaborative Group

1. Publication Details

  • Trial Title: Dexamethasone in Hospitalized Patients with Covid-19
  • Citation: RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384(8):693-704. DOI: 10.1056/NEJMoa2021436
  • Published: February 25, 2021, in The New England Journal of Medicine (preliminary report released June 2020)
  • Author: The RECOVERY Collaborative Group
  • Funding: UK Medical Research Council; National Institute for Health Research (UK); and others.

2. Keywords

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

3. The Clinical Question

  • In adult patients hospitalized with suspected or confirmed COVID-19 (Population), does treatment with dexamethasone (Intervention) compared to usual care alone (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Early in the COVID-19 pandemic, it became clear that many patients developed a severe hyper-inflammatory state leading to ARDS and death. Corticosteroids, with their potent anti-inflammatory effects, were a logical potential therapy. However, their use in other viral pneumonias was controversial due to concerns about delayed viral clearance.
  • Knowledge Gap: There was an urgent and critical need for high-quality evidence from a large, pragmatic randomized trial to determine if corticosteroids were beneficial or harmful in patients hospitalized with COVID-19.
  • Proposed Hypothesis: The authors hypothesized that dexamethasone would be superior to usual care in reducing 28-day mortality in patients hospitalized with COVID-19.

5. Study Design and Methods

  • Design: A very large, multicenter, pragmatic, adaptive platform, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 176 National Health Service (NHS) hospitals in the United Kingdom.
  • Trial Period: Enrollment for this arm of the trial ran from March to June 2020.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) hospitalized with clinically suspected or laboratory-confirmed COVID-19.
    • Exclusion Criteria: Included patients for whom the treating clinician felt dexamethasone was either definitely indicated or definitely contraindicated.
  • Intervention: Patients received dexamethasone (6 mg once daily, either orally or intravenously) for up to 10 days.
  • Control: Patients received usual care alone.
  • Management Common to Both Groups: All other aspects of care for COVID-19 were at the discretion of the treating clinicians.
  • Power and Sample Size: The trial was designed to be large enough to detect a clinically meaningful difference in mortality with a high degree of statistical certainty.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 28 days.
    • Secondary Outcomes: Included the time to discharge from the hospital and, in patients not on mechanical ventilation at randomization, the composite of invasive mechanical ventilation or death.

6. Key Results

  • Enrollment and Baseline: 6425 patients were randomized (2104 to dexamethasone and 4321 to usual care). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned, and this arm was stopped after a clear mortality benefit was demonstrated.
  • Primary Outcome: In the overall population, 28-day mortality was significantly lower in the dexamethasone group: 482 of 2104 patients (22.9%) died, compared with 1110 of 4321 patients (25.7%) in the usual-care group (p<0.001).
  • Secondary Outcomes: The benefit was greatest in the sickest patients.
    • Invasive Mechanical Ventilation: Mortality was 29.3% in the dexamethasone group vs. 41.4% in the usual-care group.
    • Oxygen Only: Mortality was 23.0% vs. 26.2%.
    • No Respiratory Support: There was no benefit; in fact, there was a trend toward harm (mortality 17.8% vs. 14.0%).
  • Adverse Events: The incidence of serious adverse events was not systematically collected in this pragmatic trial.

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 time-to-event analysis with a log-rank test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: Rate Ratio for death at 28 days: 0.83 (95% CI, 0.75 to 0.93; P-value: <0.001).
  • Interpretation of Key Statistic(s):
    • Rate Ratio (RR):
      • Calculation: The paper reports the age-adjusted result as 0.83.
      • Clinical Meaning: The RR of 0.83 means that patients in the dexamethasone group had a 17% lower relative risk of dying at 28 days compared to the usual-care group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.75 to 0.93.
      • Clinical Meaning: Since this entire range is well below the line of no effect (1.0), it confirms that the result is highly statistically significant.
    • P-value: The p-value of <0.001 is extremely low, indicating the result is highly statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR) (in ventilated patients):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 41.4% – 29.3% = 12.1%.
      • Clinical Meaning: For every 100 ventilated patients with COVID-19 treated with dexamethasone, about 12 additional deaths were prevented.
    • Number Needed to Treat (NNT) (in ventilated patients):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.121 = 8.3, which is rounded down to 8.
      • Clinical Meaning: You would need to treat only 8 ventilated patients with COVID-19 with dexamethasone to prevent one additional death.
  • Subgroup Analyses: The pre-specified subgroup analysis based on the level of respiratory support at randomization was the most critical finding of the trial, showing clear benefit in patients requiring oxygen and harm in those who did not.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, pragmatic, randomized design was a major strength, allowing a definitive answer to be generated with unprecedented speed during a pandemic.
  • Generalizability: The pragmatic design with very broad inclusion criteria makes the findings highly generalizable to the real-world population of patients hospitalized with COVID-19.
  • Statistical Power: The enormous sample size provided definitive power to detect a clear mortality benefit and to reliably assess effects in important subgroups.
  • Patient-Centered Outcomes: The primary outcome of 28-day mortality is a robust, objective, and highly relevant endpoint.

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 highly generalizable.
  • Other: The pragmatic design meant that detailed data on adverse events like secondary infections were not collected.

10. Conclusion of the Authors

  • The authors concluded that in patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone, but not among those receiving no respiratory support.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It was the first study to show a clear, life-saving benefit for any therapy in COVID-19 and immediately established dexamethasone as the global standard of care for hospitalized patients requiring respiratory support.
  • Specific Recommendations:
    • Patient Selection: For adult patients hospitalized with COVID-19 who require supplemental oxygen or mechanical ventilation.
    • Actionable Intervention: Administer dexamethasone (6 mg daily for up to 10 days).
    • Expected Benefit: This intervention can be expected to prevent approximately one death for every 8 ventilated patients treated, and one death for every 25 patients treated with oxygen alone.
  • What This Trial Does NOT Mean: This trial does NOT mean that all patients with COVID-19 should receive steroids. The clear signal of harm in patients not requiring oxygen is a critical finding.
  • Implementation Caveats: The key is to treat the right patients (those with hypoxemia) and avoid treating the wrong ones (those without hypoxemia).

12. Context and Related Studies

  • Building on Previous Evidence: The RECOVERY trial (2020) was designed to rapidly test multiple potential therapies for COVID-19. Its dexamethasone arm was likely influenced by the positive results of the earlier DEXA-ARDS trial (2020) in non-COVID ARDS.
  • Influence on Subsequent Research: The definitive positive result of this trial was a major turning point in the pandemic. It has been the cornerstone of all subsequent COVID-19 treatment guidelines and has spurred a great deal of research into the role of other immunomodulatory therapies.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal dose and duration of corticosteroid therapy in different phenotypes of COVID-19 remain areas of investigation.
  • Future Directions: The success of dexamethasone has shifted the focus of research towards identifying which patients might benefit from additional or different types of immunomodulatory therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest possible relevance, addressing a novel and devastating global pandemic with an inexpensive, widely available therapy.
  • Methods: The very large, multicenter, pragmatic RCT design was a triumph of clinical research, enabling a definitive answer to be generated with unprecedented speed. The main methodological weakness is the open-label design, but the primary outcome of mortality is objective and unlikely to be biased.
  • Results: The study reported a statistically significant and clinically profound mortality benefit in the target population. The subgroup analysis showing a clear difference in effect based on respiratory support was a critical and robust finding that allowed for a nuanced and safe application of the therapy.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in the history of medicine and public health, and its findings are directly responsible for saving hundreds of thousands of lives worldwide.

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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