September 5, 2020

It’s Raining Steroids in COVID-19: REMAP-CAP, CoDEX, & CAPE COVID

Background: Over the past few years, corticosteroids have gained traction in the treatment of patients with ARDS and septic shock.  Trials such as APROCCHSS and ADRENAL have shown that the use of corticosteroids is associated with more rapid resolution of shock, weaning from mechanical ventilation in septic shock, and, potentially lower mortality. The RECOVERY trial, the largest RCT to date on the use of corticosteroids in COVID-19, showed treatment with dexamethasone (6mg/d for 10 days)  had an absolute mortality reduction of 11% in patients receiving mechanical ventilation   (IMV) (NNT = 9), 3.5% decreased mortality in patients requiring O2 but not IMV (NNT = 29) and an overall mortality reduction 3% (NNT = 3) compared to usual care alone.  However, there was a signal toward harm (not statistically significant) in patients not receiving respiratory support.

In the September 2020 issue of JAMA, there were 3 RCTs (REMAP-CAP, CoDEX, & CAPE COVID) assessing corticosteroid therapy in critically ill patients with COVID-19, as well as a prospective meta-analysis. All 3 RCTs halted enrollment in June 2020 after the RECOVERY trial press release.  The prospective meta-analysis from the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) working group pooled data from 7 trials (RECOVERY, REMAP-CAP, CoDEX, CAPE COVID, and 3 additional trials) with roughly 1700 patients.

In this post we will review the REMAP-CAP, CoDEX, and CAPE COVID trials, as well as the prospective meta-analysis.

REMAP-CAP

Paper: REMAP-CAP Investigators. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA 2020. [Epub Ahead of Print]

Clinical Question: Does intravenous hydrocortisone administered as a 7-day fixed dose course or restricted to when shock is clinically evident, improve 21-day organ support-free days in patients with severe COVID-19?

What They Did:

  • Randomized, Open-Label, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP)
  • Adaptive platform trial testing multiple interventions with multiple therapeutic domains
    • 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an ICU for respiratory or cardiovascular organ support at 121 sites in 8 countries
    • 403 patients were randomized to open-label interventions within the corticosteroid domain
    • Trial terminated early after publication of the RECOVERY trial
  • Patients randomized to:
    • Fixed Dose: 7-day course of intravenous hydrocortisone (50mg or 100mg q6hrs
      • Only 2 patients received the 100mg regimen
    • Shock Dose: course restricted to 50mg q6hrs when shock was clinical evident
      • Stopped once shock resolved or vasopressors discontinued for 24hrs
    • No Steroids: No hydrocortisone

Outcomes:

  • Primary: Organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days
    • Bayesian cumulative logistic model
    • Superiority defined as posterior probability of an odds ratio >1 (threshold for trial conclusion of superiority >99%)
    • 5d difference considered to be the minimal clinically important difference
  • Secondary:
    • In-hospital mortality
    • ICU and hospital LOS
    • Respiratory support-free days
    • Cardiovascular organ support-free days
    • Compositive outcome of progression to IMV, ECMO, or death among patients not ventilated at baseline
    • WHO ordinal scale (Range 0 to 8) assessed at day 14
      • 0 = no illness
      • 1 – 7 = increasing level of care
      • 8 = death

Inclusion:

  • ≥18 years of age
  • Presumed or confirmed SARS-CoV-2
  • Admitted to the ICU for respiratory or cardiovascular organ support
    • Respiratory organ support = invasive or noninvasive mechanical ventilation or HFNC (flow rate ≥30LPM and FiO2 ≥0.4)
    • Cardiovascular organ support = intravenous infusion of any vasopressor or inotrope

Exclusion:

  • Presumption of death being imminent
  • Hypersensitivity to hydrocortisone
  • Systemic corticosteroid use
  • >36hrs elapsed since ICU admission

Results:

  • 384 patients included in the analysis
    • Mechanical ventilation: 50.0% to 63.5%
    • Received at least one dose of hydrocortisone:
      • Fixed Dose = 97%
      • Shock Dose = 43%
      • No Steroids = 15%
    • Median Organ Support-Free Days Within 21d (Primary Outcome):
      • Fixed Dose: 0d (Range -1 to 15)
      • Shock Dose: 0d (Range -1 to 13)
      • No Steroid: 0d (Range -1 to 11)

  • Median adjusted OR and Bayesian probability of superiority compared to no steroids were:
    • Fixed Dose: 1.43 (9% CI 0.91 to 2.27) and 93%
    • Shock Dose: 1.22 (95% CI 0.76 to 1.94) and 80%
  • Median Respiratory Support-Free Days:
    • Fixed Dose: aOR 1.42 (Bayesian probability of superiority 94%)
    • Shock Dose: aOR 1.28 (Bayesian probability of superiority 85%)
  • Median Cardiovascular Organ Support-Free Days:
    • Fixed Dose: aOR 1.63 (Bayesian probability of superiority 98%)
    • Shock Dose: aOR 1.29 (Bayesian probability of superiority 86%)

  • 21d Mortality:
    • Fixed Dose: 30% (aOR 1.03; 95% CI 0.53 to 1.95)
    • Shock Dose: 26% (aOR 1.10; 95% CI 0.58 to 2.11)
    • No Steroid: 33%
  • Median Organ Support-Free Days Among Survivors:
    • Fixed Dose: 11.5
    • Shock Dose: 9.5
    • No Steroid: 6
  • Serious Adverse Events:
    • Fixed Dose: 4 (3%)
    • Shock Dose: 5 (3%)
    • No Steroid: 1 (1%)

Strengths:

  • Asks a clinically important question
  • Nearly complete follow up of all patients (i.e. few losses to follow up)
  • Pragmatic, international design increasing generalizability of results to real world practice
  • 379 (99%) of patients completed study and included in analysis
  • Used a dose of hydrocortisone that has similar glucocorticoid equivalence to the dexamethasone dose used in RECOVERY

Limitations:

  • Open-label design; patients, physicians, and staff were not blinded to which arm each patient was enrolled in which introduces bias
  • 15% of no corticosteroid group received systemic corticosteroids which could bias results toward a smaller effect size
  • Trial ended early and did not enroll enough patients for initially planned power
  • Convenience sample of patients, non-consecutive enrollment
  • Patients in the fixed dose and shock dose groups appeared sicker to the no steroid group: More vasopressor support and higher APACHE II score

Author Conclusion: “Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days.  However, the trial was stopped early, and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.” 

Clinical Take Home Point: The use of hydrocortisone in patients with severe COVID-19, was suggestive of improvement in organ support free days within 21 days.  However, due to early trial stoppage, no treatment strategy met the prespecified criteria for statistical superiority, precluding a definitive conclusion.

CoDEX

 Paper: Tomazini BM et al. 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. JAMA 2020. [Epub Ahead of Print]

Clinical Question: In patients with COVID-19 and moderate or severe ARDS, does intravenous dexamethasone plus standard care increase the number of days alive and free from mechanical ventilation vs standard care alone?

What They Did:

  • COVID-19 Dexamethasone (CoDEX) Trial
  • Multicenter, randomized, open-label, clinical trial conducted in 41 ICUS in Brazil
  • Trial stopped early following results of the RECOVERY trial
  • Patients randomized to:
    • 20mg dexamethasone IV qD x5d, then 10mg dexamethasone IV qD x5d (or until ICU discharge) + standard care
    • Standard care alone

Outcomes:

  • Primary: Ventilator-free days during the first 28 days
    • Alive and free from mechanical ventilation for at least 48 consecutive hours
  • Secondary:
    • All-cause mortality at 28d
    • Clinical status of patients at day 15 using 6-poing ordinal scale
    • ICU-free days during the first 28 days
    • Mechanical ventilation duration at 28d
    • SOFA score at 48hr, 72hr, and 7d

Inclusion:

  • ≥18 years of age
  • Confirmed or suspected COVID-19 infection
  • Receiving mechanical ventilation within 48hrs of meeting criteria for moderate to severe ARDS (P/F ratio ≤200)

Exclusion:

  • Pregnancy or active lactation
  • Dexamethasone allergy
  • Corticosteroid use in the past 15d for nonhospitalized patients
  • Use of corticosteroids during the present hospital stay for more than 1d
  • Indication for corticosteroid use for other clinical conditions (i.e. refractory septic shock)
  • Use of immunosuppressive drugs, cytotoxic chemotherapy in the past 21d
  • Neutropenia due to hematological or solid malignancies with bone marrow invasion
  • Consent refusal
  • Expected death in the next 2hr

Results:

  • 299 patients enrolled
    • Median duration of dexamethasone treatment was 10d
    • Standard Care Group: 52 pts (35.1%) received at least 1 dose of corticosteroids
    • Median time since symptom onset to study drug ≈9d
    • 9% of patients receiving vasopressors at the time of randomization
  • Mean Ventilator-Free Days During the First 28d (Primary Outcome):
    • Dexamethasone: 6.6 (95% CI 5.0 to 8.2)
    • Standard Care: 4.0 (95% CI 2.9 to 5.4)
    • Unadjusted Difference 2.26; 95% CI 0.2 to 4.38; p = 0.04

  • Mean SOFA Score at 7d:
    • Dexamethasone: 6.1 (95% CI 5.5 to 6.7)
    • Standard Care: 7.5 (95% CI 6.9 to 8.1)
    • Unadjusted Difference -1.16; 95% CI -1.94 to -0.38; p = 0.004
  • No difference in all-cause mortality at 28d, ICU-free days during the first 28d, mechanical ventilation duration at 28d, or the 6 point ordinal scale at 15d
    • There was however a trend toward improved mortality:
      • Dexamethasone: 56.3%
      • Standard Care: 61.5%
      • HR 0.97; 95% CI 0.72 to 1.31; p = 0.85
    • Adverse Events:
      • Secondary Infections:
        • Dexamethasone: 33pts (21.9%)
        • Standard Care: 43pts (29.1%)
      • Need for Insulin for Glucose Control:
        • Dexamethasone: 47pts (31.1%)
        • Standard Care: 42pts (28.3%)
      • Serious Adverse Events:
        • Dexamethasone: 5pts (3.3%)
        • Standard Care: 9pts (6.1%)

Strengths:

  • All patients completed follow-up
  • Groups were well balanced at baseline, including severity of ARDS
  • Adverse events data regarding corticosteroid use was provided

Limitations:

  • Open-label trial design, allowed for physicians, patients, and individuals assessing outcomes to know assigned treatment
  • The difference between groups of 2.26d was lower than the effect size of 3 days used in the sample size calculation
  • Study underpowered for secondary outcomes (i.e. mortality)

Discussion:

  • Remdesivir was not available in Brazil during the trial period. Additionally, other therapeutic strategies such as tocilizumab and convalescent plasma were limited and not widely available
  • Although the mortality difference was not statistically significant in this study, there was a trend toward improvement with corticosteroids. If this was a larger study, it is possible that a 5% difference is real which would be clinically significant
  • Ventilator settings were similar between groups

Author Conclusion: “Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.”

Clinical Take Home Point: In patients with COVID-19 and moderate or severe ARDS, the use of intravenous dexamethasone plus standard care increased the number of ventilator-free days over 28 days.  Due to early stoppage, the trial was not powered to assess mortality.

CAPE COVID

Paper: Dequin PF et al. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA 2020. [Epub Ahead of Print]

Clinical Question: Does low-dose hydrocortisone decrease treatment failure in patients with COVID-19-related acute respiratory failure?

What They Did:

  • Community-Acquired Pneumonia: Evaluation of Corticosteroids in Coronavirus Disease (CAPE COVID)
  • Multicenter, randomized double-blind sequential trial conducted in France
  • Patients admitted to the ICU for COVID-19 related acute respiratory failure
  • Trial intended to enroll 290 patients but was terminated early following the recommendation of the data and safety monitoring board
  • Patients randomized to:
    • Low-Dose Hydrocortisone: continuous intravenous infusion dose of 200mg/d until day 7, then decreased to 100mg/d for 4 days, and then 50mg/d for 3 days (Total of 14d)
      • If patients respiratory and general status had sufficiently improved by day 4, a short treatment regimen was used (200mg/d for 4d, followed by 100mg/d for 2d, and then 50mg/d for 2 days – Total of 8d)
      • Had to meet all the following criteria to receive short course:
        • Patient spontaneously breathing
        • P/F ratio >200
        • SOFA score on day 4 ≤ SOFA score on day 1
        • Strong probability of being discharged from the ICU before day 14
      • Placebo: saline

Outcomes:

  • Primary: Treatment failure on day 21
    • Death or persistent dependency on mechanical ventilation or high-flow oxygen therapy
  • Secondary:
    • Need for tracheal intubation (among patients not intubated at baseline)
    • Cumulative incidences (until day 21) of prone position sessions, ECMO, and inhaled nitric oxide
    • P/F ratio measured daily from day 1 to day 7, then on days 14 and 21
    • Proportion of patients with secondary infections during their ICU stay

Inclusion:

  • ≥18 years of age
  • Admitted to ICU for acute respiratory failure
  • Confirmed or suspected SARS-CoV-2
  • Treatment administered within 24hrs of onset of the first severity criterion or within 48hrs for patients referred from another hospital
  • One of 4 severity criteria present:
    • Need for mechanical ventilation with a PEEP of ≥5cmH20
    • P/F ratio <300 on HFNC with an FiO2 of at least 50%
    • P/F ratio <300 for patient receiving O2 through a reservoir mask
    • Pulmonary Severity Index >130

Exclusion:

  • Septic shock
  • Do not intubate orders

Results:

  • 149 patients enrolled
    • 2% mechanically ventilated
    • 6% of patients with confirmed SARS-CoV-2
    • Median duration of symptoms prior to randomization was ≈9d
    • Median duration of study treatment for hydrocortisone was 10.5d
  • Treatment Failure on Day 21 (Primary Outcome):
    • Hydrocortisone: 32/76 (42.1%)
    • Placebo: 37/73 (50.7%)
    • Difference -8.6%; 95.48% CI -24.9% to 7.7%; p = 0.29

  • Of the 4 prespecified secondary outcomes, none had a significant difference
    • Mortality, although not statistically different, trended toward benefit with hydrocortisone:
      • Hydrocortisone: 14.7%
      • Placebo: 27.4%
      • Difference -12.7%; 95% CI -25.7 to 0.3%; p = 0.06
    • No serious adverse events were related to the study treatment

Strengths:

  • Double-blind randomized controlled trial
  • 3% of patients completed the study 

Limitations:

  • Study terminated after 149 patients enrolled and, thus, underpowered to find significant differences in outcomes

Discussion:

  • ≈35% of patients were receiving Hydroxychloroquine + azithromycin
  • ≈14% of patients were receiving Lopinavir-ritonavir
  • Much like CoDEX there wasn’t a statically significant difference in mortality, but a trend toward benefit. Again, a much larger trial may have found statistical significance.
  • Authors state that a dose of 6mg of dexamethasone is approximately equivalent to 160mg of hydrocortisone

Author Conclusion: “In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome.”

Clinical Take Home Point: This study did not show a reduction in treatment failure with use of low-dose hydrocortisone compared to placebo at day 21 but this may be due to the early stoppage of the study.

Prospective Meta-Analysis

Paper: 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. [Epub Ahead of Print]

Clinical Question: Is the administration of systemic corticosteroids associated with reduced 28-day mortality in critically ill patients with COVID-19?

What They Did:

  • Prospective meta-analysis pooling data from 7 RCTs that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19
    • A prospective meta-analysis is a collaborative research design in which individual sites perform RCTs and pool the data for meta-analysis
  • Trials conducted in 12 countries
  • Patients randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678pts) or receive usual care or placebo (1025pts)

Outcomes:

  • Primary: All-cause mortality at 28d after randomization
  • Secondary: investigator-defined serious adverse events

Results:

  • 7 RCTs with 1703 patients

  • 28d All-Cause Mortality (Primary Outcome)
    • 5 trials reported mortality at 28d, 1 trial at 21d, and 1 trial at 30d
    • Corticosteroids: 222/678 (32.7%)
    • Placebo or Usual Care: 425/1025 (41.5%)
    • Summary OR 0.66; 95% CI 0.53 to 0.82; p < 0.001

  • Dexamethasone vs Usual Care of Placebo
    • 3 trials, 1282pts, and 527 deaths
    • Summary OR 0.64 (95% CI 0.50 to 0.82; p <0.001)
  • Hydrocortisone vs Usual Care or Placebo
    • 3 trials, 374pts, and 94 deaths
    • Summary OR 0.69 (95% CI 0.43 to 1.12; p = 0.13
  • Methylprednisolone
    • 1 trial, 47pts, and 26 deaths
    • Summary OR 0.91 (95% CI 0.29 to 2.87; p = 0.87)

  • Adverse Events (6 trials reported)
    • Corticosteroids: 64/354 (18.1%)
    • Usual Care or Placebo: 80/342 (23.4%)

Strengths:

  • Large number of critically ill patients with COVID-19 from geographically diverse sites
  • Primary outcome is patient oriented and determined before any outcome data were available from any of the studies
  • All subgroup analyses (with the exception of shorter vs longer duration of symptoms at randomization) were all pre-specified

Limitations:

  • Corticosteroid-induced complications could not be analyzed reliably due to the number of studies reporting serious adverse events and their definitions/methods of assessment varying among trials
  • Trials were mainly conducted in high-income settings
  • The RECOVERY trial contributed 57% of the weight in the primary meta-analysis of 28-day all-cause mortality

Discussion:

  • There does not seem to be evidence suggesting that a higher dose of corticosteroids is associated with greater benefit than a lower dose of corticosteroids
  • Benefit associated with corticosteroids appeared greater in critically ill patients not on IMV at randomization, but based on 4 trials and 144 patients
  • Risk of bias of the individual trials

Author Conclusion: “In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo was associated with lower 28-day all-cause mortality.”

Clinical Take Home Point: In critically ill patients with COVID-19, administration of systemic corticosteroids vs usual care or placebo is associated with a lower 28-day all-cause mortality

The Bottom Line:

  • All 3 RCTs reviewed here were terminated early due to the results of the RECOVERY Trial and only CAPE COVID was a blinded RCT
  • Administration of systemic corticosteroids vs usual care or placebo is associated with lower 28d all-cause mortality in critically ill patients with COVID-19 pneumonia
  • Corticosteroids should be a standard component of care for critically ill patients with COVID-19 (i.e. Low Flow O2, HFNC, NIV, IMV, ECMO)
  • Questions Remaining:
    • Optimal dose and duration of corticosteroids
    • Use of biomarkers to help decide on initiation of corticosteroids
    • True incidence of adverse effects from corticosteroids
    • Combination of corticosteroids with other medications (i.e. antivirals)

References:

  1. REMAP-CAP Investigators. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA 2020. [Epub Ahead of Print]
  2. Tomazini BM et al. 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. JAMA 2020. [Epub Ahead of Print
  3. Dequin PF et al. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA 2020. [Epub Ahead of Print]
  4. 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. [Epub Ahead of Print]
  5. Prescott HC et al. Corticosteroids in COVID-19 ARDS: Evidence and Hope During the Pandemic. JAMA 2020 [Epub Ahead of Print]

For More Thoughts on This Topic Checkout:

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

Cite this article as: Salim Rezaie, "It’s Raining Steroids in COVID-19: REMAP-CAP, CoDEX, & CAPE COVID", REBEL EM blog, September 5, 2020. Available at: https://rebelem.com/its-raining-steroids-in-covid-19-remap-cap-codex-cape-covid/.
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Salim Rezaie

Emergency Physician at Greater San Antonio Emergency Physicians (GSEP)
Creator & Founder of REBEL EM
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