What is the effect of dexamethasone on mortality in hospitalized, COVID-19 patients?

Comment by InpharmD Researcher

Full results from the RECOVERY trial confirm the use of dexamethasone results in lower 28-day mortality among patients hospitalized with COVID-19 who were receiving either invasive mechanical ventilation or oxygen support.
Background

Per the National Institute of Health (NIH), dexamethasone is recommended for hospitalized patients with COVID-19 who require supplemental oxygen. This is based on preliminary results from the RECOVERY trial. The NIH also mentions that one study has studied the use of intravenous dexamethasone (20 mg daily for 5 days, then 10 mg daily for 5 days or until ICU discharge) plus standard of care in patients with COVID-19 and moderate to severe acute respiratory distress syndrome. If dexamethasone is not available, alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone can be used. [1]

A meta-analysis with pooled data from seven randomized clinical trials evaluating the efficacy of corticosteroids was published in JAMA. Patients had either received dexamethasone, hydrocortisone, or methylprednisolone or usual care or placebo. The primary outcome was all-cause mortality at 28 days after randomization. The overall inverse variance–weighted fixed-effect risk ratio was 0.80 (95% CI, 0.70-0.91) for all-cause mortality comparing corticosteroids with usual care or placebo. The authors concluded that the administration of corticosteroids was associated with lower all-cause mortality at 28 days after randomization in hospitalized patients that were and were not receiving mechanical ventilation. [2]

References:

[1] National Institutes of Health. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Available at https://www.covid19treatmentguidelines.nih.gov/. Updated March 5, 2021. Accessed March 18, 2021.
[2] The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020;324(13):1330–1341. doi:10.1001/jama.2020.17023
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the effect of dexamethasone on mortality in hospitalized, COVID-19 patients?

Please see Tables 1-2 for your response.

 

Dexamethasone in Hospitalized Patients with Covid-19 (RECOVERY)

Design

Randomized, controlled, open-label, adaptive, platform trial

N=6,425

Objective

To evaluate the effects of dexamethasone in patients hospitalized with COVID-19

Study Groups

Dexamethasone (n=2,104)

Usual care (n=4,321)

Inclusion Criteria

 Clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trail

Exclusion Criteria

 Dexamethasone considered either indicated or contraindicated, dexamethasone unavailable at the hospital at time of enrollment

Methods

Eligible patients were assigned 2:1 to either usual standard of care or usual standard of care plus dexamethasone 6 mg (either PO or IV) once daily for up to 10 days (or discharge, if sooner). Participants could also be randomized to other arms of the RECOVERY trial, but these treatments are not discussed in these results.

Duration

Intervention: up to 10 days

Follow-up: 28 days

Outcome Measures

Primary outcome: all-cause mortality within 28 days of randomization

Secondary outcomes: time to discharge from hospital (within 28 days), subsequent receipt of invasive mechanical ventilation (including extra-corporeal membrane oxygenation) or death (among patients not receiving invasive mechanical ventilation at randomization)

Baseline Characteristics

  

Dexamethasone (n=2,104)

Usual care (n=4,321)

  

Age, years

 66.9±15.4 65.8±15.8  

Female

766 (36%) 1,572 (36%)  

White

 1,550 (74%) 3,139 (73%)  

Days since symptom onset (IQR)

 8 (5–13) 9 (5–13)  

Days since hospitalization (IQR)

 2 (1–5) 2 (1–5)  
IQR=interquartile range

Results

  

Dexamethasone (n=2,104)

Usual care (n=4,321)

Risk Ratio (95% CI)

Death at 28 days

No oxygen

Oxygen only

Invasive mechanical ventilation

482 (22.9%)

89/501 (17.8%)

298/1,279 (23.3%)

95/324 (29.3%)

1,110 (25.7%)

145/1,034 (14.0%)

682/2,604 (26.2%)

283/683 (41.4%)

0.83 (0.75–0.93)

1.19 (0.92–1.55)

0.82 (0.72–0.94)

0.64 (0.51–0.81)

Discharged from hospital within 28 days

 1,416 (67.3%) 2,748 (63.6%) 1.10 (1.03–1.17)

Invasive mechanical ventilation or death

 462/1,780 (26.0%) 1,003/3,638 (27.6%) 0.93 (0.85–1.01)

Invasive mechanical ventilation

 110/1,780 (6.2%) 298/3,638 (8.2%) 0.79 (0.64–0.97)

Death*

 387/1,780 (21.7%) 827/3,638 (22.7%) 0.93 (0.84–1.03)

Successful cessation of invasive mechanical ventilation

 160/324 (49.4%) 268/683 (39.2%) 1.47 (1.20–1.78)

Of those allocated to dexamethasone, 95% received at least one dose and they were treated for a median of 6 days. This is in contrast to 7% of the usual care group who received at least one dose of dexamethasone.

*excluded those on invasive mechanical ventilation at randomization

CI=confidence interval

Adverse Events

Common Adverse Events: not reported

Serious Adverse Events: Hyperglycemia, gastrointestinal hemorrhage, psychosis

Study Author Conclusions

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. 

InpharmD Researcher Critique

The size was large enough to collect enough data for the study. Information on physiologic, laboratory, or virologic measures were not collected.

This trial provides evidence that dexamethasone 6 mg once daily for up to 10 days reduced 28-day mortality among patients receiving respiratory support. Patients not receiving respiratory support saw no benefit (and the possibility of harm).

Approximately 7% of the patients were crossed over, as some of the usual care also involved dexamethasone. This was also an open-label study in a relatively sick population.



References:

RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384(8):693-704. doi:10.1056/NEJMoa2021436

 

 Dexamethasone in Hospitalized Patients with Covid-19 

Design

Controlled, randomized, open-label trial (N= 6425) 

Objective

To evaluate the effectivness of dexamethasone in patients hospitalized with Covid-19

Study Groups

The usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) (n= 2104)

The usual standard of care (n= 4321) 

Inclusion Criteria

Aged at least 18 years, Hospitalised, Confirmation of SARS-CoV-2 infection by PCR, and Pregnant or breast-feeding women 

Exclusion Criteria

In the opinion of the attending clinician, patients are excluded from the study if the clinician believes that including the patients can put the patient at significant risk if he/she were to participate in the trial

Methods

Eligible patients randomized 2:1:1:1 ratio into 4 arms. The two groups received the usual treatments, and the other group received the usual treatments plus deamethasone (oral or intravenous dexamethasone at a dose of 6 mg once daily) for 10 days and follow up call were made at day 28 

Duration

Trial duration: March 19 to June 8, 2020

Intervantion: 10 days (follow up after 28 days) 

Outcome Measures

Primary outcome: Mortality at 28 days 

Secondary outcomes: Discharge from hospital within 28 days, invasive mechanical ventilation or death, death, and invasive mechanical ventilation 

Baseline Characteristics

   Usual care plus Dexamethasone 

usual care 

 No receipt of oxygen   Oxygen only   Invasive mechanical ventilation 

Age

Mean - yr 

  66.9±15.4 65.8±15.8 69.4±17.5 66.7±15.3 59.1±11.4

Female

 36 (%) 36 (%) 42 (%) 37 (%) 27 (%)

White

  74 (%)  73 (%) 80 (%) 75 (%) 57 (%)

Black, Asian, or minority ethinic group

 17 (%) 18 (%) 12 (%) 17 (%) 29 (%)

Unknown 

 9 (%) 9 (%) 8 (%) 8 (%) 14 (%)

Coexisting disease 

 56 (%) 56 (%) 59 (%) 56 (%) 50 (%)

 

Results

Endpoint

Dexamethasone plus usual care 

Usual care 

Risk ratio (95% CI) 

    

Death at 28 days 

  482 (22.9%)  1110 (25.7%)  0.83 (0.75-0.93)     
Discaharge from hospital within 28 days 1416 (67.3%)  2748 (63.6%) 1.10 (1.03-1.17)    
Death  387 (21.7%) 827 (22.7%) 0.93 (0.84-1.03)     
 

Adverse Events

Common Adverse Events: Not disclosed 

Serious Adverse Events: hyperglycemia, gastrointestinal hemorrhage, and psychosis

Percentage that Discontinued due to Adverse Events: 0.1

Study Author Conclusions

 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

InpharmD Researcher Critique

The patient population were large which made the study to be more Creditable, however they should have made it double blind to minimize bias. Over all, the study's outcomes are similar to other research outcomes. 



References:

RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384(8):693-704. doi:10.1056/NEJMoa2021436