Dexamethasone in COVID-19 – Too Good To Ignore

RECOVERY TRIAL

The RECOVERY trial is a randomized clinical trial designed to evaluate several treatment modalities in patients with COVID-19 infection.

11,000 patients from 175 hospitals of the National Health Services.

Inclusion Criteria –

Hospitalized patients who had clinically suspected or laboratory-confirmed COVID-19 infection

Exclusion –

1. if dexamethasone was unavailable at the treating hospital or considered to be definitely indicated or contraindicated by the treating physician. The treating staff was not blinded to the study arm.

Intervention – 

Dexamethasone 6 mg once daily IV or orally for a maximum of 10 days using web-based randomization.

Patients were assigned in a 2:1 ratio to receive usual care.

Sample Size – 

The Steering Committee recommended that a sample size of 2000 patients in the intervention arm and 4000 patients in the control arm would provide the study with 90% power for a p-value of 0.11 to detect an absolute risk difference of 4% in the 28-day mortality.

Results- 

The mean age of patients was 66.1 years, and predominantly male (64%);

56% of patients had co-morbidities, including diabetes (24%), heart disease (27%), and chronic lung disease (21%).

24% of all patients did not receive any respiratory support, 60% received oxygen alone or with non-invasive ventilatory support if required, and 16% received invasive mechanical ventilation or were on extracorporeal membrane oxygenation.

Primary Outcome – 28-day mortality

Overall, the 28-day mortality was significantly lower in patients who received dexamethasone compared to those who received standard care alone (21.6% vs. 24.6%; rate ratio: 0.83, CI: 0.74–0.92, P <0.001).

Sub-Group Analysis – 

Overall, the 28-day mortality was highest among patients who received invasive mechanical ventilation (40.7%) compared to those who received oxygen alone (25%) and those who required no respiratory support (13.2%) at randomization.

The greatest reduction in mortality was seen among patients who received invasive mechanical ventilation; dexamethasone administration resulted in a reduction in mortality by 35% in this subgroup (rate ratio 0.65; 95% CI: 0.51–0.82; p <0.001).

A 20% reduction in mortality was observed among patients who received supplemental oxygen, with or without the use of non-invasive ventilation (rate ratio 0.80; 95% CI: 0.70–0.92; p = 0.002).

However, there was no difference in 28-day mortality with dexamethasone in patients who did not require respiratory support.

Secondary outcomes – 

Dexamethasone administration resulted in a statistically significant (though not clinically meaningful) reduction in the duration of hospitalization (median: 12 vs. 13 days) and a higher proportion of patients who were discharged within 28 days.

Among patients who were not invasively ventilated at enrolment, significantly fewer patients progressed to the composite outcome of invasive ventilation or death in the dexamethasone arm.

Strengths –

1. Adaptive Trial Design
2. Adequately powered trial
3. Practice changing trial
4. Good internal and external validity
5. Completed under unprecedented conditions under enormous time pressure
6. No conflict of interest from the pharmacological company
7. Cheap drug and easily available in every ICU
8. Assessed the impact of intervention according to the severity of the disease.
9. The minimum confounding effect from co-interventions

Limitations – 

1. Open-label trial
2. Baseline variability between the two groups
3. The rationale behind choosing 6 mg dose – not explained
4. Synergistic effect with other treatments remains still unknown
5. Incomplete data due to pre-publication

Summary – 

Very well conducted, a practice-changing trial which potentially might change the course of this deadly pandemic.

Guidelines regarding COVID-19 needs a major update.