Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19 The CoDEX Randomized Clinical Trial

Design

Multicenter, randomized, open label, clinical trial

N=299

Objective

To evaluate the efficacy of intravenous dexamethasone in patients with moderate to severe acute respiratory distress syndrome (ARDS) due to Coronavirus Disease (COVID)-19

Study Groups

Dexamethasone (n=151)

Standard of Care (n=148)

Methods

Inclusion Criteria: adults with confirmed or suspected COVID-19 infection receiving mechanical ventilation within 48 hours of meeting criteria for moderate to severe ARDS with a partial pressure of arterial blood oxygen to fraction of inspired oxygen (PaO₂:FIO₂) ratio of 200 or less

Exclusion Criteria: pregnancy, active lactation, corticosteroid use in the past 15 days for non-hospitalized patients, use of corticosteroid during present hospital stay for more than one day, indication for corticosteroid use for other clinical conditions, use of immunosuppressive drugs and cytotoxic chemotherapy in the past 21 days

Patients were assigned in a 1:1 ratio to receive standard of care and dexamethasone 20 mg intravenously (IV) once daily for five days followed by 10 mg IV once daily for an additional five days or until intensive care unit (ICU) discharge. Patients in the control group received standard of care only.

Duration

Follow up at 28 days

Outcome Measures

Primary outcome: ventilator-free days during the first 28 days

Secondary outcomes: all-cause mortality during the first 28 days, clinical status of patients at day 15, ICU free days during the first 28 days, mechanical ventilation duration at 28 days, and change in SOFA scores

Baseline Characteristics

Dexamethasone

(n=151)

Standard of Care

(n=148)

Age, years

Men

Days since symptom onset 

Days of mechanical ventilation prior to randomization

SARS-CoV-2 Positive

Additional Medications

Hydroxychloroquine

Azithromycin

Other Antibiotics

Oseltamivir

36 (23.8%)

104 (68.9%)

133 (88.1%)

44 (29.1%)

28 (18.9%)

109 (73.6%)

128 (86.5%)

52 (35.1%)

More than two-thirds of the study population had pre-existing conditions with the most prevalent being hypertension, diabetes, obesity, and heart failure.   

Results

Dexamethasone

(n=151)

Standard of Care

(n=148)

Days alive and ventilator-free at 28 days

Mean (95% CI)

Median (IQR)

6.6 (5.0-8.2)

0 (0 - 17)

4.0 (2.9-5.4)

0 (0-3)

28 Day Results

All-cause mortality

ICU free days

MV duration days

85 (56.3%)

2.1 (1.0-4.5)

12.5 (11.2-13.8)

91 (61.5%)

2.0 (0.8-4.2)

13.9 (12.7-15.1)

0.97 (0.72 to 1.31), p=0.85

0.28 (-0.49-1.02), p=0.50

-1.54 (-3.24-0.12), p=0.11

CI= confidence interval, IQR= interquartile range, ICU= intensive care unit, MV=mechanical ventilation

Adverse Events

Dexamethasone

(n=151)

Standard of Care

(n=148)

Absolute Difference (95% CI)

Serious Adverse Events

New Diagnosis of Infection

Ventilator Associated Pneumonia

Catheter-related bloodstream infections

5 (3.3%)

33 (21.9%)

19 (12.6%)

10 (6.6%)

9 (6.1%)

43 (29.1%)

29 (19.6%)

8 (5.4%)

2.8 (−2.7 to 8.2)

7.2 (−3.3 to 17.7)

7.0 (−2.0 to 16.0)

−1.2 (−7.3 to 4.8)

Study Author Conclusions

Dexamethasone plus standard of care versus stand of care alone significantly increased the number of days alive and free of mechanical ventilation during the first 28 days without increasing the risk of adverse events.

InpharmD Researcher Critique

Dexamethasone significantly reduced the number of days alive and free of mechanical ventilation and may one of the most promising treatment options for COVID-19.  

This trial only included patients with COVID-19 and moderate or severe ARDS. It was open-label and underpowered because the study was stopped after data from the RECOVERY trial was released. Additionally, 35% of the patients in the control group received corticosteroids during the study period.

Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report (RECOVERY)

Design

Randomized, controlled, open-label trial

N=6,425

Objective

To evaluate the efficacy and safety of potential treatment options in patients hospitalized with Covid-19

Study Groups

Dexamethasone (n=2,104)

Usual Care (n=4,321)

Methods

Inclusion Criteria: hospitalized patients with clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history, per discretion of the attending clinician

Exclusion Criteria: if dexamethasone was unavailable at time of enrollment or if steroids were contraindicated 

Patients were assigned in a 2:1 ratio to receive the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone at 6 mg per day for a maximum of 10 days (or until discharge if sooner) or to receive another available treatments being evaluated in the trial (not presented in the report). 

Duration

Follow up after 28 days

Outcome Measures

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

Secondary outcomes: Time until discharge, receipt of invasive mechanical ventilation, death, cause specific mortality, receipt of renal hemodialysis or hemofiltration, major cardiac arrhythmia, and receipt and duration of ventilation

Baseline Characteristics

Dexamethasone

(n=2,104)

Usual Care

(n=4,321)

Age, years

Men

Days since symptom onset 

Days since hospitalization

SARS-CoV-2 Positive

About 60% of patients studied had a pre-existing disease with diabetes, heart disease, and chronic lung disease being the most prevalent.  

Results

Dexamethasone

(n=2,104)

Usual Care

(n=4,321)

RR (95% CI), P-value

Mortality at 28 Days

All Patients

Invasive mechanical ventilation

Oxygen only

No oxygen received

482 (22.9%)

95 (29.3%)

298 (23.3%)

89 (17.8%)

1110 (25.7%)

283 (41.4%)

682 (26.2%)

145 (14.0%)

0.83 (0.75 – 0.93), p <0.001

0.64 (0.51-0.81)

0.82 (0.72-0.94)

1.19 (0.91-1.55)

Discharged from  hospital within 28 days

1413 (67.2%)

2745 (63.5%)

1.10 (1.03-1.17)

Invasive mechanical ventilation

102/1780 (5.7%)

285/3638 (7.8%)

0.77 (0.62-0.95)

Death

387/1780 (21.7%)

827/3638 (22.7%)

0.93 (0.84-1.03)

RR = Risk ratio, CI = Confidence Interval

Adverse Events

Not reported

Study Author Conclusions

The RECOVERY trial provides evidence that treatment with dexamethasone reduces 28 day mortality in patients on invasive and noninvasive mechanical ventilation but did not provide evidence of mortality reduction in patients without respiratory support.  

InpharmD Researcher Critique

Dexamethasone is a reasonable, inexpensive and relatively safe option in patients requiring hospitalization and respiratory support for COVID-19. Patients who did not require respiratory support did not see a benefit with dexamethasone.

These results are preliminary and this trial was open label.

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19

Design

Ongoing, international, multicenter, open-label trial

N=403

Objective

To determine whether hydrocortisone improves outcomes for patients with severe Coronavirus Disease (COVID)-19 

Study Groups

Fixed-dose hydrocortisone (n=143)

Shock-dependent hydrocortisone (n=152)

No hydrocortisone (n=108)

Methods

Inclusion Criteria: adults with presumed or confirmed COVID-19 infection who were admitted to an intensice care unit (ICU) for respiratory or cardiovascular organ support

Exclusion Criteria: presumption of imminent death, systemic corticosteroid use, more than 36 hours elapsed since ICU admission 

Patients were randomized to receive a fixed dose of intravenous hydrocortisone, 50 mg every six hours for seven days; intravenous hydrocortisone, 50 mg every 6 hours while in shock for up to 28 days; or no hydrocortisone. Hydrocortisone was discontinued in the shock-dependent group once shock was considered to have resolved or vasopressors had been discontinued for 24 hours.

Duration

Up to 21 days

Outcome Measures

Primary outcome: respiratory and cardiovascular organ support–free days up to day 21

Secondary outcomes: hospital mortality, ICU and hospital length of stay, respiratory support free days, cardiovascular organ support free days, a composite outcome of progression to invasive mechanical ventilation (MV),  extracorporeal membrane oxygenation (ECMO) or death among those not ventilated at baseline, and the World Health Organization (WHO) ordinal scale assessed at day 14

Baseline Characteristics

Fixed-dose hydrocortisone (n=137)

Shock-dependent hydrocortisone (n=146)

No hydrocortisone (n=101)

Age, years

 60.4 ± 11.6

59.5 ± 12.7

59.9  ±14.6

Men

98 (71.5%)

103 (70.6%)

72 (71.3%)

Confirmed SARS-CoV-2 Infection

109/134 (81.3%)

87/125 (69.6%)

79/100 (79.0%)

Time to Enrollment (IQR)

From hospital admission, days

From ICU admission, hours

1.2 (0.8-2.6)

15.1 (7.5-19.8)

1.0   (0.7-2.8)

12.3(5.4-18.8)

1.1(0.7-2.0)

13.5 (8.1-17.5)

Acute Respiratory Support

None

High-flow nasal cannula

Noninvasive MV

Invasive MV

ECMO

Vasopressor support

0

17 (12.4%)

33 (24.1%)

87 (63.5%)

1/137 (0.7%)

56 (40.9%)

1 (0.7%)

23 (15.8%)

49 (33.6%)

73 (50.0%)

0/143

47 (32.2%)

0

16 (15.8%)

32 (31.7%)

53 (52.5%)

2/99 (2.0%)

30 (29.7%)

Results

Fixed-Dose Hydrocortisone (n=137)

Shock-Dependent Hydrocortisone (n=146)

No Hydrocortisone (n=101)

Organ Support Free Days

Adjusted OR (n=576)

Mean

Median

Probability of superiority to no hydrocortisone

0 (-1 to 15)

1.47 ± 0.35

11.5 (0 to 17)

93%

0 (-1 to 13)

1.26 ± 0.31

1.22 ( 0.76 to 1.94)

80%

0 (-1 to 11)

1 [Reference]

1 [Reference]

Hospital Deaths

Adjusted OR

Mean

Median (95% CI)

Probability of superiority to no hydrocortisone

41 (30%)

1.08 ± 0.37

1.03 (0.53-1.95)

54%

37 (26%)

1.16 ± 0.40

1.10 (0.58-2.11)

62%

33 (33%)

1 [Reference]

1 [Reference]

OR = Odds Ratio, CI= Confidence Interval

Adverse Events

Patients with >1 serious adverse events

4 (3%)

5 (4%)

1 (1%)

Study Author Conclusions

In patients with severe COVID-19, treatment with a 7 day fixed course of hydrocortisone or shock-dependent dosing of hydrocortisone was 93% and 80% superior, respectively, to no hydrocortisone treatment in improvement of organ support free days. However, this study was stopped early and no statistical superiority was met.  

InpharmD Researcher Critique

The use of hydrocortisone in patients with severe COVID-19 may be superior to no hydrocortisone treatment in terms of organ support free days including respiratory and cardiovascular support.

These results were reported before meeting any prespecified internal trigger. This trial was open label and 15% of patients in the “no hydrocortisone” group received systemic corticosteroids.

Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Design

Randomized, controlled clinical trial

N=149

Objective

To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with Coronavirus Disease (COVID)-19 and acute respiratory failure

Study Groups

Hydrocortisone (n=76)

Placebo (n=73)

Methods

Inclusion Criteria: adults with presumed or confirmed COVID-19 admitted for acute respiratory failure, with one of four severity criteria: need for mechanical ventilation with a positive end-expiratory pressure (PEEP) of  ≥5 cm; a ratio of PaO₂ to fraction of inspired oxygen (FIo2) less than 300 on high-flow oxygen therapy with an FIO₂ value of at least 50%; for patients receiving oxygen through a reservoir mask, a PaO₂:FIO₂ ratio < 300; or a Pulmonary Severity Index (PSI) greater than 130

Exclusion Criteria: septic shock and do not intubate orders 

Patients were randomized in a 1:1 ratio to receive a continuous intravenous infusion of hydrocortisone at an initial dose of 200 mg/day or placebo (saline). Treatment was continued until day 7 and then decreased to 100 mg per day for four days and 50 mg per day for three days for a total of 14 days.

Duration

21 days

Outcome Measures

Primary outcome: treatment failure on day 21, defined as death or persistent dependency on mechanical ventilation or high flow oxygen therapy

Secondary outcomes:  use of tracheal intubation, use of prone position, extracorporeal membrane oxygenation (ECMO) or inhaled nitric oxide, the PaO₂:FIO₂ ratio recorded daily from day 1 to day 7 and then on days 14 and 21; and the proportion of patients with nosocomial infections recorded during the ICU stay

Baseline Characteristics

Hydrocortisone (n=76)

Placebo (n=73)

Age, years

63.1 (51.5-70.8)

66.3 (53.5-72.7)

Men

54 (71.1%)

50 (68.5%)

Respiratory support at Inclusion

Mechanical Ventilation

High Flow Oxygen

Non-rebreathing mask

62 (81.6)

10 (13.2%)

4 (5.3%)

59 (80.8%)

9 (12.3%)

5 (6.8%)

Concomitant Therapy

Hydroxychloroquine

Hydroxychloroquine + Azithromycin

Ritonavir-lopinavir

11 (14.5%)

23 (30.3%)

10 (13.2%)

8 (11.0%)

28 (38.4%)

11 (15.1%)

Results

Placebo (n=73)

Difference in proportions (95% CI)

P-value

Treatment Failure on Day 21

37 (50.7%)

-8.6 % (-24.9 to 7.7)

0.29

Secondary Outcomes

Endotracheal Intubation

ECMO

Inhaled Nitric Oxide

Nosocomial infections (day 28)

8/16 (50%)

2 (2.7%)

5 (6.7%)

28 (37.7%)

12/16 (75.0%)

2 (2.7%)

11 (15.0%)

30 (41.1%)

HR 0.81 (0.49 to 1.35)

0.42

Post Hoc Outcomes (Day 21)

Death

Mechanical Ventilation

11 (14.7%)

17 (22.7%)

20 (27.4%)

17 (23.3%)

-12.7 (-25.7 to 0.3)

0.057

HR= Hazard ratio, CI= Confidence Interval

Adverse Events

Three serious adverse events were reported, all in the hydrocortisone group; cerebral vasculitis possibility related to SARS-CoV-2, cardiac arrest related to a pulmonary embolism, intraabdominal hemorrhage related to anticoagulant therapy for pulmonary embolism

Study Author Conclusions

In this randomized clinical trial that was terminated early, hydrocortisone, compared with placebo, did not significantly reduce the rate of treatment failure, defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy, among critically ill patients with COVID-19.

InpharmD Researcher Critique

Low dose hydrocortisone, compared to placebo, did not significantly reduce treatment failure in critically ill patients with COVID-19 and acute respiratory failure.

This underpowered trial was terminated early after the press release of the dexamethasone trial and the data provided for the nosocomial infections were not adjudicated.