Podcast #205 - Return of Dexamethasone: Appraisal of the Pre-Print COVID-19 Article

Surprisingly, we are back already to talk about dexamethasone.  Our last podcast, #204, covered the press release from the RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial and their mentioning of results regarding dexamethasone.  Now, the study is available in a pre-print form.  It is important that this has not yet been peer-reviewed and is still preliminary, but we now have some real information that we can review!

 Title:
Horby, et al. Effect of Dexamethasone in Hospitalized Patients with COVID-19 – Preliminary Report​ 
 
Case:
You are treating a patient with COVID-19 that has been intubated, sedated, and on invasive mechanical ventilation (IMV) but continues to worsen.  A recent paper has been discussed in the news about an old and established corticosteroid that may help, dexamethasone.  You question if this may help save your patient's life and if this should be used for this patient.
 
Background:
The COVID-19 pandemic has been devastating and treatment has been controversial.  Until this time, no medications had shown improvement in survival.  Dexamethasone has been discussed in previous podcasts including #24 covering single dose dexamethasone in adult asthma, #53 on oral dexamethasone for sore throats, and #121 when discussing the management of croup.   COVID-19 has also been discussed before on podcasts #189, #190, #192, #193, #194, #195, #196, #197, #199, and #200 in addition to our last podcast.
 
Clinical Question:
Does dexamethasone (IV or PO) + usual care reduce 28 day mortality in patients hospitalized with COVID-19 compared to usual care alone?
 
Reference:

• Population: Clinically suspected or laboratory confirmed SARS-CoV-2 infection, with 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 trial, that were ≥18 years of age (age limit removed on May 9th, 2020), and could be pregnant or breast-feeding women.  
  • Exclusion Criteria: Nothing stated in the manuscript.
• Intervention: Dexamethasone (IV or PO) 6 mg daily for 10 days + usual care. 
• Comparison: Usual care alone.
• Outcome: The primary outcome was 28 day mortality (Pre-specified subgroup analysis of those patients on O2, IMV, and those getting neither).

 
Author’s Conclusions:
“In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization but not among patients not receiving respiratory support.”
 
Quality Checklist for Randomized Clinical Trials:

1. The study population included or focused on those in the ED. Not directly as these are critical care patients.
2. The patients were adequately randomized. Yes
3. The randomization process was concealed. Yes
4. The patients were analyzed in the groups to which they were randomized. Yes
5. The study patients were recruited consecutively (i.e. no selection bias). Unsure, but appears to be that way based on some of the wording
6. The patients in both groups were similar with respect to prognostic factors. Yes
7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No, this was done as an open-label study
8. All groups were treated equally except for the intervention. Yes
9. Follow-up was complete (i.e. at least 80% for both groups). Yes
10. All patient-important outcomes were considered. Yes, with the most important being mortality which was the primary outcome
11. The treatment effect was large enough and precise enough to be clinically significant. Yes

 
Key Results:
2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001, fragility index [FI] 18, number needed to treat [NNT] of 33.3). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001, FI 17, NNT 8.5), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002, FI 8, NNT 28.6), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14).  No FI or NNT calculated with the last group since it was not statistically significant based on the p-value.

Key Points of Debate:

• A sample size could not be calculated.
  • Given the unique and novel nature of COVID-19, this should be no surprise.
  • A steering committee, blinded to the results of the study formed a “best guess” of 2000 vs 4000 patients with an estimated 28-day mortality of 20% could detect an absolute difference of 4% between the two groups.
  • If this is all true, this is great because they went above the goals of the steering committee. 
• This was an open-label study which could bias results.
  • However, with 28-day mortality being the primary outcome, it is difficult to have bias.
  • Someone is either dead or alive which makes this an excellent binary outcome that avoids bias.
  • There is the potential effect though of people receiving dexamethasone getting a higher level of care compared to those not receiving the medication.
• Those receiving dexamethasone were 1.1 years old than those in the usual care arm.
  • While technically statistically significant, this is most likely not clinically significant.
  • This is most likely an example of random chance and not a true signal.
  • The authors accounted for this imbalance with adjustment for baseline age and gave results with and without age-adjustment which showed it did not alter the conclusions.
• Some patients were excluded due to lack of dexamethasone availability or the managing physician said it was contraindicated.
  • It is unclear how many were excluded from this analysis, but it appears to be approximately 17% based on the results section.
  • This leads to an uncertainty on how this would affect results.
• 7% of the “usual care” group received dexamethasone. 
  • However, the data was analyzed on an intention-to-treat principle. 
  • The 7% crossover would tend to reduce the potential benefit of dexamethasone.
• Mortality  benefit improves with worsening disease.
  • This data suggests that the worse the patient is doing, the more likely they are to benefit from receiving dexamethasone.
  • The sicker the patient, the more likely a patient should receive dexamethasone.
• Those not needing oxygen and treated with dexamethasone did worse than the usual care group not receiving dexamethasone.
  • This could be related to the phase of the illness.
  • Immunosupression with dexamethasone could worsen the disease when given too early in someone's illness.
  • This would suggest that dexamethasone is not a medication that should be given in all patients.
• Patients with >7 days of symptoms did better than patients ≤7 days.  
  • Timing may be an important part of dexamethasone administration. 
  • This could be related to the phase that the disease process is in.
  • Indication creep is common, but in COVID-19 with dexamethasone this could be deadly if people receive dexamethasone too early and in not as severe of condition as those patients that benefited in this study.

Comparing Conclusions:
We agree that in hospitalized patients with COVID-19, dexamethasone reduces 28-day mortality especially in those receiving IMV and to a lesser degree those receiving oxygen alone.  It does not appear to help those not receiving respiratory support.
 
Our Bottom Line:
This was a well done RCT for patients with COVID-19 pneumonia.  It appears, based on the study that has not yet been peer reviewed, that dexamethasone does significantly improve 28-day mortality for those requiring respiratory support.  This is especially true if they are requiring IMV.  
 
Case Resolution:
You have a discussion with the family by phone to discuss options for management.  With shared decision making they elect to start dexamethasone treatment.  Thanks to great critical care (and potentially the dexamethasone) your patient is able to successfully recover and survive their ordeal with COVID-19.
 
Clinical Application:
While this is a preliminary report it appears that patients requiring any oxygen therapy, HFNC, NIV, IMV, or ECMO would benefit from dexamethasone.  However, we must be mindful that further evidence could later disprove this benefit and we should continue to monitor the literature.
 
What do I tell my patient?
With your patient being intubated and sedated, there is not much you can tell them.  However, you can speak with the family.  You explain to the family that there is a steroid named dexamethasone that has been studied and based on the current evidence it has demonstrated that it can save lives in those requiring respiratory support.  It is important to emphasize that the evidence may change with time and that there are other factors that can play a role in saving someone's life with COVID-19 pneumonia.
 
Conclusion:
This study has been incredibly popular and several posts have already been made including by REBEL EM, FOAMcast, and Broome Docs.   Feel free to check these out and make sure to read the article yourself! ​

​Let us know what you think by giving us feedback here in the comments section or contacting us on Twitter or Facebook.  Remember to look us up on Libsyn and on Apple Podcasts.  If you have any questions you can also comment below, email at thetotalem@gmail.com, or send a message from the page.  We hope to talk to everyone again soon.  Until then, continue to provide total care everywhere.

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