RECOVERY (Covid-19)

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Horby P, et al. "Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report". The New England Journal of Medicine. 2020. e-pub 2020-07-17:1-11.
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Clinical Question

In patients hospitalized with Covid-19, does the addition of dexamethasone improve survival compared to usual care?

Bottom Line

In patients hospitalized with Covid-19, dexamethasone 6 mg/d for up to 10 days improved 28-day survival in the subset of patients receiving supplemental oxygen or mechanical ventilation.

Major Points

In the early days of the Covid-19 pandemic, clinicians and investigators scrambled to develop effective therapies for patients, particularly those with severe disease in whom the case fatality rate was very high. Authors of mechanistic studies, case reports, retrospective studies, and clinical guidelines advocated for remdesivir, hydroxychloroquine, antiretrovirals, anticoagulants, and other therapies on the basis of limited data which at best was hypothesis-generating. As randomized data became available, it became clear that many of these treatments were modestly effective if at all: remdesivir improved time to recovery but did not impact survival,[1][2] hydroxychloroquine did not improve clinical outcomes when given as Covid-19 therapy[3] or as postexposure prophylaxis,[4] and the antivirals lopinavir-ritonavir were ineffective.[5] Steroids had been proposed as well, but a well designed, randomized study was needed to demonstrate their efficacy in Covid-19.

Published in 2020, the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial aimed to determine whether oral or intravenous dexamethasone reduced 28-day mortality in patients hospitalized with COVID-19. This randomized, open-label, multi-center controlled trial assigned patients in a 2:1 ratio to receive either usual care or usual care plus dexamethasone (at a dose of 6 mg once daily, either PO or IV) until hospital discharge or up to 10 days. A total of 9,355 patients (83%) were eligible to receive dexamethasone, and of these 6,425 were randomly assigned to dexamethasone or placebo. Follow-up was available for 6,418 (99.9%) of participants. Patients in the dexamethasone arm had a significantly lower 28-day mortality, which was the primary endpoint of the study (22.9% vs. 25.7%; RR 0.83; P<0.001). A subgroup analysis demonstrated that this benefit was limited to patients receiving supplemental oxygen (23.3% vs. 26.2%; RR 0.82) or mechanical ventilation (29.3% vs. 41.4%; RR 0.64). Consequently, the number needed to treat to save one life at 28 days was 34 among patients receiving supplemental oxygen, and 8 among patients receiving mechanical ventilation. The authors note the lack of benefit, and possibility of harm, of dexamethasone in patients not receiving respiratory support.

RECOVERY was well designed and executed, and efficiently communicated results by press release,[6] then preprint,[7] and subsequently in manuscript form on 17 Jul 2020. The study's findings were incorporated into guidelines shortly thereafter.

Guidelines

NIH Covid-19 Treatment Guidelines (2020, adapted)[8]

  • The panel recommends dexamethasone 6 mg/d for up to 10 days for the treatment of Covid-19 in patients receiving mechanical ventilation (recommendation level A, evidence I) and in patients receiving supplemental oxygen but who are not mechanically ventilated (BI).
  • The panel recommends against dexamethasone for patients who do not require supplemental oxygen (AI).
  • If dexamethasone is unavailable, the panel recommends an alternative agent such as prednisone, methylprednisolone, or hydrocortisone (AIII).

Design

  • Open label, randomized, multi-center trial
  • N=6,425 patients hospitalized with Covid-19
    • Dexamethasone (n=2,104)
    • Placebo (n=4,321)
  • Setting: 176 National Health Service organizations in the UK
  • Enrollment: March-June 2020
  • Analysis: Intention-to-treat
  • Primary outcome: 28-day mortality

Population

Inclusion Criteria

  • Age ≥18 years (subsequently age limit was removed)
  • Clinically suspected or laboratory confirmed Covid-19
  • No medical history that might put patients at risk if they were to participate in the trial
  • Pregnant women were eligible

Exclusion Criteria

  • Inability to provide informed consent

Baseline Characteristics

From the dexamethasone group.

  • Median age: 66.9 years
  • Female sex: 36%
  • Median days since symptom onset: 8
  • Median days since hospitalization: 2
  • Respiratory support: no oxygen 24%, oxygen only 61%, mechanical ventilation 15%
  • Comorbidity: any 56%, diabetes 25%, heart disease 28%, chronic lung disease 20%, TB 6%, HIV 12%, severe liver disease 2%, severe kidney disease 8%
  • Covid-19 confirmed: 88%

Interventions

  • Patients were randomized 2:1 to usual care or dexamethasone, or one of the other treatments offered on the study.
    • Dexamethasone group received dexamethasone 6 mg/d IV or PO until hospital discharge or up to 10 days

Outcomes

Comparisons are dexamethasone vs. usual care.

Primary Outcomes

28-day mortality
22.9% vs. 25.7% (rate ratio [RR] 0.83; 95% CI 0.75-0.93; P<0.001)

Secondary Outcomes

Discharged from hospital within 28 days
67.2% vs. 63.5% (RR 1.10; 95% CI 1.03-1.17)
Risk of progression to mechanical ventilation
5.7% vs. 7.8% (RR 0.77; 99% CI 0.62-0.95)
Death
21.7% vs. 22.7% (RR 0.93; 95% CI 0.84-1.03)

Subgroup Analyses

28-day mortality among mechanically ventilated patients
29.3% vs. 41.4% (RR 0.64; 95% CI 0.51-0.81)
28-day mortality among supplemental oxygen patients
23.3% vs. 26.2% (RR 0.82; 95% CI 0.72-0.94)
28-day mortality among patients not receiving respiratory support
17.8% vs. 14.0% (RR 1.19; 95% CI 0.91-1.55)

Criticisms

  • None

Funding

  • Medical Research Council
  • National Institute for Health Research
  • Others

Further Reading

  1. Wang Y et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020. 395:1569-1578.
  2. Wang Y et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020. 395:1569-1578.
  3. Tang W et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ 2020. 369:m1849.
  4. Boulware DR et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N. Engl. J. Med. 2020. 383:517-525.
  5. Cao B et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N. Engl. J. Med. 2020. 382:1787-1799.
  6. "Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19". 16 Jun 2020. 
  7. "Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial.". 15 Jul 2020. 
  8. "COVID-19 Treatment Guidelines".