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Corticosteroid, Dexamethasone Improves Survival in COVID-19: Deaths reduction by 1/3 in ventilated patients and by 1/5 in other patients receiving oxygen only


Corticosteroid, Dexamethasone Improves Survival in COVID-19: Deaths reduction by 1/3 in ventilated patients and by 1/5 in other patients receiving oxygen only

Reporter: Aviva Lev-Ari, PhD, RN – bold face and color fonts added

 

UPDATED on 6/28/2020

https://public.tableau.com/profile/matt.chadsey#!/vizhome/Corona_15895153725490/TreatmentSummary

Corona – COVID19 Treatment Registry

Viz Author: Matt Chadsey

CORONA is the COVID19 Registry of Off-Label & New Agents. A project of the Center for Cytokine Storm Treatment & Laboratory (CSTL) and the Castleman Disease Collaborative Network (CDCN).

10,553 Views  4

Inspiration:

Originally Published:

May 15, 2020

Last Updated:

Jun 27, 2020

Workbook Details:

11 Sheets

Metadata:

https://public.tableau.com/profile/matt.chadsey#!/vizhome/Corona_15895153725490/TreatmentSummary

SOURCE

The Castleman Disease Research Network publishes Phase 1 Results of Drug Repurposing Database for COVID-19

Reporter: Stephen J. Williams, PhD.

https://pharmaceuticalintelligence.com/2020/06/27/the-castleman-disease-research-network-publishes-phase-1-results-of-drug-repurposing-database-for-covid-19/

Paul Sax
@PaulSaxMD

If you’re wondering whether to use dexamethasone for patients presenting with COVID19 who need oxygen as we await the publication of the RECOVERY trial, here’s one opinion (mine): Yes. Latest post: blogs.jwatch.org/hiv-id-observa

Dexamethasone Improves Survival in COVID-19 – Why This Should Be Practice-Changing Even Before the…
When the news broke last week that the dexamethasone component of the RECOVERY randomized clinical trial was halted because those receiving the drug were significantly more likely to survive, I…
blogs.jwatch.org
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104
239

Paul Sax
@PaulSaxMD

The favorable dexamethasone data for covid19 will likely amplify the already apparent increased risk for aspergillosis among these critically ill people. Plenty of work for experts like

and others.

Image

Paul Sax
@PaulSaxMD
– Very welcome news, dex is cheap, widely available! – Demonstrates the power of RCTs vs obs studies, which were conflicting – How will the numerous ongoing studies of immunomodulators be modified? – Rx guidelines — act now or wait for more info?
Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe…
Statement from the Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on dexamethasone, 16 June 2020
recoverytrial.net

Note my last point, about “guidelines”. These committees have a responsibility to get what they recommend right, and might be slower than clinicians to recommend an intervention with limited information — even if it is potentially life-saving.

But my assumption was that clinical practice would change quickly, awaiting the updating of guidelines. After all, this is what we’ve been waiting for — data from a randomized trial demonstrating a clear benefit. Even better, it’s a readily available, inexpensive strategy — a course of corticosteroids — familiar to us all.

I confess the responses to my post, and comments elsewhere, surprised me. Lots of skepticism. Wow.

The comments fell into several interrelated categories:

Let’s wait for the study to be peer-reviewed and published in an established medical journal before changing clinical practice.

Really? Even when the sickest patients — those requiring oxygen or ventilatory support — were more likely to survive?

(Yes, I keep italicizing that endpoint. Emphasis, you know.)

For the record, here are the results:

Dexamethasone reduced deaths by

  • one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by
  • one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021).

When a study stops because of a survival benefit for a life-threatening disease, take note. It’s because continuing the study as originally designed is unethical — those randomized to receive “usual care” would be deprived of a potentially life-saving treatment.

The steering committee has a responsibility of ensuring the safety of trial participants. And remember, they have access to all the study data, even if we don’t. Credit: NIAID

It’s critical that this information be made available as soon as possible. Patients are being treated today who might benefit, and writing papers and subsequent peer review take time — typically weeks, even with the “warp speed” of COVID-19.

To quote one of the investigators: “Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.”

Well said.

Why are we getting critical information via press release? I’m inherently distrustful. A press release doesn’t represent actual data.

It’s reasonable to be skeptical of clinical trial press releases, especially when issued by private pharmaceutical companies with multi-million dollar marketing divisions.

These notoriously exaggerate the importance of study results, especially when focused on surrogate markers of disease that may or may not predict clinical outcome.

But consider — this isn’t a press release by a giant company, citing a minor change in an inflammatory cytokine or quality-of-life metric in an open-label study. It’s a respected clinical trials group, funded by the government of Great Britain, and they are reporting a survival benefit from their clinical trial.

To their credit, they early on started doing randomized trials of various COVID-19 interventions while the rest of the globe practiced the therapeutic equivalent of throwing drugs against the wall hoping some of them would stick.

  • Lopinavir-ritonavir!
  • Interferons!
  • Oseltamivir!
  • Hydroxychloroquine!
  • Azithromycin!
  • Ivermectin!

And it’s not just antimicrobials — virtually every immunomodulator under the sun, some extremely expensive, has found its way to off-label use for critically ill patients with COVID-19.

  • Tocilizumab!
  • Sarilumab!
  • Anakinra!
  • Ruxolitinib!
  • Eculizumab!
  • Any-other-mab! And more …

Yes, it’s hard to keep up — see Table 1 in this recent review for all the various anti-inflammatory approaches tried off-label, with many of these now under study.

If we’re using some of these unproven therapies — and many of us have — why not dexamethasone, which in the RECOVERY trial improved survival?

Here we go again! Haven’t we been burned already multiple times with research on COVID-19, only later to have this information questioned, or retracted?

Quite reasonable to be cautious in this very fast-moving area.

But the infamous research that has “burned” us involved much weaker levels of evidence — little more than anecdotal observations at one extreme and observational studies with likely falsified data at the other.

None has been a randomized clinical trial with a survival benefit.

(Have I noted that result enough times already? Nah.)

I need more details about the study. What were the primary endpoints? The specifics of the intervention? What were the patient characteristics of those enrolled? Did some subgroups benefit more than others? What were the toxicities? 

All very reasonable questions! But good news — we have the full protocol available for review. This can answer some of these queries, including the endpoints and description of the exact interventions studied.

https://blogs.jwatch.org/hiv-id-observations/index.php/dexamethasone-improves-survival-in-covid-19-why-this-should-be-practice-changing-even-before-the-paper-is-published/2020/06/21/?query=C19

 

RRFERENCES

Statement from the Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on dexamethasone, 16 June 2020

https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19

SOURCE

https://blogs.jwatch.org/hiv-id-observations/index.php/dexamethasone-improves-survival-in-covid-19-why-this-should-be-practice-changing-even-before-the-paper-is-published/2020/06/21/?query=C19

Other Related Studies

Countermeasures to COVID-19: Are immunomodulators rational treatment options — a critical review of the evidence 

Open Forum Infectious Diseases, ofaa219, https://doi.org/10.1093/ofid/ofaa219
Published:
05 June 2020

Article history

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with higher concentrations of pro-inflammatory cytokines which leads to lung damage, respiratory failure, and resultant increased mortality. Immunomodulatory therapy has the potential to inhibit cytokines and quell the immune dysregulation. Controversial data found improved oxygenation after treatment with tocilizumab, an IL-6 inhibitor, sparking a wave of interest and resultant clinical trials evaluating immunomodulatory therapies. The purpose of this article is to assess potential pro-inflammatory targets and review the safety and efficacy of immunomodulatory therapies in managing patients with acute respiratory distress syndrome associated with COVID-19.

Conclusions from PDF Full Article Version

SARS-CoV-2 leads to ALI and ARDS with increased mortality. Immunomodulatory therapies have the potential to inhibit cytokines, but the role of elevated cytokines with lung pathology is unclear. The overall lack of evidence and recommendations has forced practitioners to use their own judgment regarding use of immunomodulatory therapy. We are hopeful that as clinical trial data become available their role in managing patients with COVID-19 will emerge. For now, available evidence suggests these treatment options be reserved for use in critically ill COVID-19 patients enrolled in clinical trials. Due to the potential adverse effects, risks and benefits must be weighed and proper screening completed prior to use.

This content is only available as a PDF.

About the RECOVERY trial

The RECOVERY trial is a large, randomised controlled trial of possible treatments for patients admitted to hospital with COVID-19. Over 11,500 patients have been randomised to the following treatment arms, or no additional treatment:

  • Lopinavir-Ritonavir (commonly used to treat HIV)
  • Low-dose Dexamethasone (a type of steroid, which typically used to reduce inflammation)
  • Hydroxychloroquine (which has now been stopped due to lack of efficacy)
  • Azithromycin (a commonly used antibiotic)
  • Tocilizumab (an anti-inflammatory treatment given by injection)
  • Convalescent plasma (collected from donors who have recovered from COVID-19 and contains antibodies against the SARS-CoV-2 virus).

Overall dexamethasone reduced the 28-day mortality rate by 17% (0.83 [0.74 to 0.92]; P=0.0007) with a highly significant trend showing greatest benefit among those patients requiring ventilation (test for trend p<0.001). But it is important to recognise that we found no evidence of benefit for patients who did not require oxygen and we did not study patients outside the hospital setting. Follow-up is complete for over 94% of participants.

The RECOVERY Trial is conducted by the registered clinical trials units with the Nuffield Department of Population Health in partnership with the Nuffield Department of Medicine. The trial is supported by a grant to the University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR) and by core funding provided by NIHR Oxford Biomedical Research CentreWellcome, the Bill and Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council Population Health Research Unit, and NIHR Clinical Trials Unit Support Funding.

The RECOVERY trial involves many thousands of doctors, nurses, pharmacists, and research administrators at over 175 hospitals across the whole of the UK, supported by staff at the NIHR Clinical Research Network, NHS DigiTrials, Public Health England, Public Health Scotland, Department of Health & Social Care, and the NHS in England, Scotland, Wales and Northern Ireland.

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