Critical Care, Critical Care Alert, COVID-19

Critical Care Alert: Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19. The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial

Critical Care Alert

Article
Investigators TWCftR-C. 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;Sept. 2:online-first.

Objective
To determine whether hydrocortisone improved outcomes for patients with severe COVID-19.

Background
SARS-CoV-2 (coronavirus 2019, COVID-19) shook the medical community off its base. The dichotomy between the benignity of some patients clinical courses juxtaposed to the critical nature of others was extremely unsettling. For the latter group, the medical community at large grasped at virtually anything that could offer clinical benefit: trialing anti-malarial medications, antibiotics, anti-virals, and so-on. One avenue investigated robustly was administration of corticosteroids in critically ill patients with confirmed COVID-19.

We know from previous studies that there is no clear consensus on the use of steroids in critically ill sepsis patients. There are only weak recommendations.

  • The ADRENAL trial published in 2018 in NEJM looked at 3658 patients in septic shock and who were intubated. They found no statistically significant difference in 90 day mortality in those who received hydrocortisone vs those who did not; they did, however, see reduced time to wean off ventilation and reduced overall ICU stay. 2
  • The APROCCHSS trial published as well in 2018 in NEJM evaluated 1241 patients in septic shock. However, in this study there was a mix of intubated and non-intubated patients. Study investigators found that there was a reduction in 90 day mortality with hydrocortisone + fludrocortisone. Additionally, they also saw the same trend in a reduced time to wean off ventilation and reduced overall ICU stay. 3

Regarding steroid use in patients with acute respiratory distress syndrome (ARDS), in 2018 Meduri et. al published a trial in The Journal of Intensive Care demonstrating that a prolonged course of methylprednisolone treatment reduced duration of mechanical ventilation and mortality in patients with ARDS. 4

More recently in 2020, the DEXA-ARDS trial was published in The Lancet which was a multi-center trial investigating the use of dexamethasone in patients with clinical ARDS. Here they found increased numbers of ventilator-free days and a reduction in all-cause mortality at 60 days. Important to note is that this trial had a number of significant limitations including that it was unblinded. 5

With the mixed results and relatively benign safety profile, it is of no surprise there has been large interest in the role of steroids in patients with COVID.

Design
Take a deep breath with this one. The REMAP-CAP trial employs a  novel study design that is complicated. This is a randomized, embedded, multifactorial, adaptive, platform (REMAP) study being performed on an international (8 countries) , multicenter (121 sites), open-label basis.

Patients are randomized to different interventions within a single domain, or therapeutic class. For example, patients in this specific clinical trial were randomized to one of three dosing regimens within the domain of hydrocortisone therapy.The 3 randomized classes were:

  1. 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hrs)
  2. Shock-dependent course (50 mg every 6 hrs when shock was clinically evident)
    1. Resolution of shock determined clinically or by discontinuation of vasopressors for 24 hrs
  3. No hydrocortisone

Other therapeutic domains within the REMAP-CAP trial focused on antivirals or antibiotics (as examples).

Trial Selection
Inclusion Criteria:

  • 18 years of age or older
  • Confirmed or suspected SARS-CoV-2
  • Admitted to an intensive care unit
  • Requiring respiratory support (invasive or non-invasive)
  • Requiring cardiovascular support (needing vasopressors or inotropes)

Exclusion Criteria

  • Presumed imminent death
  • Hypersensitivity to hydrocortisone
  • Systemic corticosteroid use
  • >36 hours elapsing from ICU admission

Primary Outcome

  • Days alive and free of ICU-based cardiopulmonary support within 21 days of randomization

Secondary Outcomes

  • In-hospital mortality
  • ICU length of stay
  • Hospital length of stay
  • Respiratory support-free days
  • Cardiovascular organ support–free days,
  • Composite outcome of:
    • Progression to invasive mechanical ventilation
    • Extracorporeal membrane oxygenation (ECMO)
    • Death among those not ventilated at baseline
    • World Health organization (WHO) ordinal scale at day 14

Key Results
Unlike many other trials, the REMAP-CAP trial employed Bayesian analysis, looking for the probability that one intervention is superior or not to another. Please check out The Bottom Line for a good overview on Bayesian Statistics.

Total number of patients included in analysis: 614 patients out of 1165 screened

Primary Outcomes:

  • Median organ support–free days were 0 (IQR, –1 to 15), 0 (IQR, –1 to 13), and 0 (IQR, –1 to 11)
    • Of note - a value of (-1) was used as the outcome for death within the hospital for the primary outcomes.
  • Analysis of primary outcome with covariate data from all severe COVID-19 patients in the REMAP-CAP trial noted:
    • Median adjusted odds ratios of 1.43 (95% CrI, 0.91-2.27) and 1.22 (95% CrI, 0.76-1.94) for the fixed-dose and shock-dependent groups, respectively → associated with a 93% and 80% probability of superiority when compared to no hydrocortisone administration.

Selected Secondary Outcomes :

  • In-hospital mortality
    • Median adjusted odds ratios of 1.03 (95% CrI, 0.53-1.95) and 1.10 (95% CrI, 0.58-2.11) for the fixed-dose and shock-dependent groups, respectively → associated with a 54% and 62% probability of superiority when compared to no hydrocortisone administration.
  • Quick-bits: percent probability of superiority of fixed and shock dependent hydrocortisone compared to no hydrocortisone
    • ICU length of stay (29% vs 14%)
    • Hospital length of stay (43% vs 31%)
    • Respiratory support-free days (94% vs 85%)
    • Cardiovascular organ support–free days (98% vs 86%)
  • Composite outcome of progression to invasive mechanical ventilation OR extracorporeal membrane oxygenation (ECMO) OR death among those not ventilated at baseline. (99% vs 70%)
  • World Health organization (WHO) ordinal scale at day 14. (87% vs 55%)

Strengths

  • Large number of critically ill patients
  • Pragmatic, international, mult-center design
  • International steering committee were blinded
  • Use of bayesian results

Limitations

  • Trial Stopped early after RECOVERY data demonstrated mortality benefit with dexamethasone
  • Neither interventional group met pre-specified internal statistical significance triggers prior to trial stoppage
  • Open label
  • 15% of those in non-hydrocortisone group received systemic steroids
  • Clinical staff not blinded to treatments
  • < half of the shock group received a single dose of hydrocortisone

EM Take-Aways
In this study, which again is an analysis of a single treatment domain within a larger study platform, study authors demonstrated the high probability of superiority of corticosteroid use compared to no steroids with respect to organ support free days within the first 21 days of treatment in patients suffering from COVID-19 and requiring cardiopulmonary support in an ICU. However the study was stopped early due to the publication of the RECOVERY trial, and none of the strategies meet the prespecified criteria for statistical superiority.  Taken in conjunction with results from other recently published studies (WHO Meta-analysis and RECOVERY), use of steroids may be warranted in this patient population.

Quick plug for the  Critical Care Reviews podcast on this trial, which does a great job ironing out all the components of this complicated and impressive study design and timeline. Discussion on bayesian statistics included!

Also feel free to check out the REMAP-CAP website for more information.


References

  1. Investigators TWCftR-C. 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;Sept. 2:online-first.
  2. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378(9):797-808.
  3. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809-18.
  4. Meduri GU, Siemieniuk RAC, Ness RA, Seyler SJ. Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS. J Intensive Care. 2018;6(1):53.
  5. Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. The Lancet Resp Med. 2020 Mar 1;8(3):267-76.

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