>> Howard Bauchner: Hello and welcome to "Conversations
with Dr. Bauchner. It is Howard Bauchner,
Editor in Chief of "JAMA". And it's rare that
I find myself proud of something that our
journal is doing. You know, we have a responsibility
each day to present good and high quality
research to the world but this is a particularly
unique day. Simultaneously we are publishing
five papers and the WHO is releasing a document
entitled "Corticosteroids for COVID-19, A
Living Guidance" 2 September 2020. I'm joined
today by a number of individuals who have
been part of this remarkable effort. Jonathan
Sterne who is the lead author on a meta-analysis
which I'll explain in a bit. Jonathan is a
Professor of Medical Statistics and Epidemiology
at Bristol Medical School. Todd Rice who,
along with Hallie Prescott, has summarized
the three randomized clinical trials and the
meta-analysis that are all being published
simultaneously in "JAMA" as we speak in an
editorial. And Janet Diaz. Janet is the head
of the Clinical Care Group within WHO Emergencies
Program, and Janet and her group has been
responsible for this document. But before
we start and I ask each of them to make some
introductory comments, I wanted to inform
our viewers and our listeners what we're actually
publishing today. So there are three randomized
clinical trials. There's a single meta-analysis
and then there is an editorial. So the first
clinical trial, The Effect of Hydrocortisone
on 21-Day Mortality or Respiratory Support
Among Critically Ill Patients With COVID-19,
A Randomized Clinical Trial. First author
is Pierre-Francois Dequin for the CAPE COVID
Trial Group and the CRICS-TriGGERSep Group.
This is a study that intended to enroll 290
patients, was stopped early after the announcement
of recovery, ultimately enrolling about 150
patients. This study was done in France. The
second study, Bruno Tommasini and Luciano
Azevedo are the first and senior authors.
This is from Brazil. The Effect of Dexamethasone
on Days Alive and Ventilator-Free in Patients
with Moderate or Severe Acute Respiratory
Distress Syndrome and COVID-19, the Co-DEX
Randomized Clinical Trial. This study included
299 patients. And the third clinical trial,
The Effect of Hydrocortisone on Mortality
and Organ Support in Patients With Severe
COVID-19, the REMAP-CAP COVID-19 Corticosteroid
Domain Randomized Clinical Trial. The writing
group, the REMAP-CAP Writing Committee, corresponding
author is Derek Angus. This study, it ultimately
enrolled 384 patients, conducted in 121 sites
in eight countries. And the meta-analysis,
Jonathan led the effort. The writing group,
the WHO Rapid Evidence Appraisal for COVID-19
Therapies REACT Working Group. The title of
the meta-analysis, Association Between Administration
of Systemic Corticosteroids and Mortality
Among Critically Ill Patients With COVID-19,
a Meta-Analysis. I must thank the peer reviewers.
Each peer reviewer saw all four papers. They
conducted peer review in two days or three
days. These manuscripts were processed at
JAMA because the authors, our Senior Editors,
our editorial group and the authors worked
daily, each day, over three weeks to make
sure that we could publish all five articles
simultaneously. Jonathan, what do the results
say?
>> Jonathan Sterne: Thanks, Howard. And thanks
very much for the introduction. And I should
probably mention in addition to the groups
that you've mentioned the work here was led
by Srin Murthy and John Marshall who have
been part of the WHO Clinical Characterization
Group with Janet and who started convening
the trial investigators way back in April.
And perhaps mention the investigators of three
trials who you haven't mentioned so far, Bindu,
steroid [inaudible] trial in China, Jesus
Sevilla, and Anders Perner who also led trials
and also contributed to the effort. Everybody
watching will know that the only drug demonstrated
to reduce mortality in COVID-19 is dexamethasone
and that we learned that on the sixteenth
of June when the Recovery trial, a very large
UK-based trial, released its results. At that
time the investigations of nearly all the
world's trials of corticosteroids in critically
ill, the sickest with COVID-19, were already
talking about a collaboration where they would
pool and rapidly disseminate their results.
And once the Recovery trial had published,
it was agreed that that was what would be
done. We agreed that the last date for recruitment
would be the ninth of June so that patients'
care couldn't have been affected by the release
of Recovery results and that meant that the
last day for follow-up, the 28-day mortality,
was the sixth of July. And, as you know because
you've been part of this process, Howard,
subsequent to that the trials rapidly combined
their data and we perhaps mention that it's
really unprecedented. The trials are taking
a big risk when they share their data in advance
of publication because then the concern that
any trial team will have is that if their
data were published by someone, their own,
their paper will be less interesting. So in
the spirit of trust and because of the urgency
of these results for the care of patients
worldwide, the trial [inaudible] and shared
their data [inaudible] get the meta-analysis,
everybody wrote their papers at the same time
and we were able to [inaudible] the paper
within two weeks to JAMA and it has been a
real pleasure working with you and your colleagues
to get [inaudible] finished and to get us
publication, too. [Inaudible] show the bottom
line is that these are the sickest patients
who are being treated with corticosteroids
in these trials and [inaudible] is very high.
It's about 40% in the absence of treatment
with corticosteroids. The treatment with corticosteroids
reduces mortality of 40% to 32%. That's a
20% relative reduction, or, if you like to,
and a better way to think about it, an easier
way to think about it is that out of every
100 patients treated with corticosteroids
eight additional patients do not die. And
the final way to think about it is that approximately
for every patient, 12 patients that you treat,
you save one life and that's really the bottom
line from these results.
>> Howard Bauchner: Janet, two questions for
you and then I'll go to Todd. The first is
how did you pull it off? And then what does
the new WHO guidelines recommend? So the first
is how did you get everyone to cooperate?
It's not something that we often do. We're
in the middle of a pandemic and I really have
to thank all of the investigators, and I want
to echo something that Jonathan said, there's
more than these three clinical trials in the
meta-analysis but lets, you have to read the
paper to see what's in it. But, Janet, how
did WHO pull it off and what do the new guidelines
say?
>> Janet Diaz: Well, thank you so much, Howard.
It's actually a privilege and a pleasure to
be here and it's kind of, it's unbelievable
almost that we actually made to the end. And
so I think to start with we do want to say
thank you to all the collaborators [inaudible]
internally to WHO with my good colleague,
John Grove, who leads the Quality Assurance
for Norms and Standards, really a key member
of our group here, to the Methods Supports
Team that worked with us, the External Methods
Support Team and that's the MAGIC Ecosystem
Foundation so both Francois Lamontagne who
is our Methods chair, and [Inaudible] also
from MAGIC. And then, of course, to all the
trialists as you already described and what
Jonathan added on. Really for me it was something
that we knew we wanted to bring evidence,
you know, science to the bedside. So how quickly
can we bring good science to inform patient
care? You know, as WHO, we want to write,
you know, evidence-based guidelines. We want
to bring the best practices to the field,
especially to member state, to all our member
states, and especially into countries that
really rely on our guidance, that don't produce
their own national guidance, that don't have
their own processes or national societies
that will make trustworthy and transparent
guidances, as well as the policy makers who
are looking to support countries and procurement
and distribution of lifesaving medicines.
So that was the impetus and we knew from the
beginning, even from February, that we wanted
to prioritize corticosteroids because we knew
people were going to start using corticosteroids,
you know, without, because it was around,
and we like to do that in intensive care,
some people like to do that in intensive care,
and that we should just take this opportunity
to study it. And so luckily many investigators
started to study it and we saw this fantastic
opportunity then can we bring the investigators
together and try to make, pool analysis, that
idea of a prospective meta-analysis, and,
you know, is this possible? So we ventured
on this experiment. And, of course, I want
acknowledge Srin Murthy and John Marshall,
you know, our good colleagues who chair the
WHO Clinical Research Working Group where
our focus was on clinical characterization
research and clinical management research.
And we together, you know, reached out to
the investigators and started to convene on
a weekly basis the development of this protocol
and then Jonathan joined our team. And I think
it was just really with the good nature of
everyone, with the transparency, with the
trust that we had in each other and in the
process. And I think, thinking of the patient
at the bedside, I think we were, you know,
all of the PIs are, most of them are intensivists
working in busy ICUs, understanding that we
need to bring good evidence to inform guidance,
and I think just were superb in the collaboration
effort to help WHO, to work with WHO. And
there was quite a bonding experience in the
process that we went through. And then I think
from the getting the evidence, pooling it
together, from the technical side, then rapidly
trying to package, you know, convene the GDG
which, of course, I wanted to acknowledge.
There's 23 of them and they're all in the
guideline, then you can see who they were
but really them being able to see data, give
us good feedback, see more data even though
it was unpublished data, we received data
early and I think that was also a new, an
innovative, an important process. So the manuscripts
were not published when we saw them. So we
saw the data early. That allowed us to start
the process, wait until the manuscripts were
peer reviewed and submitted, and refine our
guidance. But at least we were able to start
early so by the time all these studies were
going to become public, we were able to actually
then also produce our guidance. And then I
have to thank you at JAMA for the collaborative,
for the collaboration as well, understanding
the need for doing good reviews but doing
them quickly and really just the collaborative
effort that everyone took part in their part
of this puzzle as we were trying to put the
puzzle together. So in regards to what does
the guidance say, so there are two recommendations
in the guidance but it is, it's about eighteen
pages long I think with graded evidence, with
the summary of findings tables, and so, and
all the description of the trials, but the
evidence says the recommendations are for,
one, a strong recommendation for the use of
corticosteroids in patients with severe or
critical COVID-19, and that is evidence, and
that is a strong recommendation. It is based
on a moderate certainty for the reasons of
the absolute risk reductions that Jonathan
already explained. The second recommendation
is for a recommendation against the use of
corticosteroids in mild COVID-19. And that
recommendation was based on low certainty
of evidence but with a concern there could
be increased deaths with the use of corticosteroids
in patients with mild COVID-19. So the guidance
itself, those are the highlights. The guidance
itself goes through the entire process of
how we convened the meetings, the discussions
around things, and a lot of things about practical
[inaudible], practicalities around implementation
and also limitations and things that need
to be addressed for the future so thank you.
>> Howard Bauchner: Thanks, Janet. So, Todd,
you with Hallie Prescott have written the
editorial that summarizes the three clinical
trials, the meta-analysis. The title of the
editorial is Corticosteroids in COVID-19 ARDS,
Evidence and Hope During the Pandemic. So,
as Jonathan said, 8 per 100 treated lives
saved, about nominated to treat 1 in 12. So
why did it work, Todd? Why, after 20 years
of research of steroids and sepsis, steroids
and ARDS, why do think it's worked?
>> Todd Rice: Yeah, well, [inaudible], Howard.
No, okay. You know, I mean, I think that this
is a disease that has phases and the initial
phase is damage done by the virus. And then
I think it's becoming more and more clear
that a later phase of this disease is dominated
by an inflammatory component and hyperinflammation.
And I think steroids are very good at decreasing
that inflammatory component and reducing the
damage and the effects of hyperinflammation
in the body. And it think that's probably
the mechanism although we don't know for sure,
that's probably the mechanism as to how the
steroids are working [inaudible].
>> Howard Bauchner: Now one of the questions
that's already come in, it's addressed in
the meta-analysis and in your editorial, is
hydrocortisone or dexamethasone. And, Jonathan,
I'll return to you because there's going to
be a big issue around the world because every
country doesn't have both. Both the WHO recommendation
as well as the meta-analysis goes into dose.
I think that's a little less critical than
actually hydrocortisone or dexamethasone.
But, Todd, could you comment about whether
or not there's a, do you have a sense if there's
a preference for one over the other?
>> Todd Rice: Yeah. My take on these data
are that it appears to be a class effect and
that it's from the steroids and not from a
specific steroid, dexamethasone or hydrocortisone.
And [inaudible] to what's the steroid that
you have, that you can easily get, and that's
what you should use. The effect sizes appear
to be very similar between dexamethasone and
hydrocortisone. And I don't think, based off
these data, that you could say there's a preference
for one over the other.
>> Howard Bauchner: Jonathan and Janet, Jonathan,
is that your reading of the data, and, Janet,
was that the conclusion of the guideline work
group for WHO? So, Jonathan, you first.
>> Jonathan Sterne: Yes, absolutely. So the
estimated effect of hydrocortisone, as Todd
said, was very similar and consistent with
the estimated effects of dexamethasone, although,
because fewer patients had been randomized
in trials of hydrocortisone, the confidence
interval was wider, but the effects were very
consistent. One trial and then one additional
trial that we located late had randomized
patients to a third steroid, methylprednisolone,
and there there are certainly sufficiently
few patients randomized that the effect is
imprecisely estimated and the truth is we
just don't know. But I think one of the reasons
that these results are very good news worldwide
is that it really says that there are two
options. And, as Todd says, it's hard to choose
between dexamethasone and hydrocortisone.
They are both routinely used in critical care
and therefore if one isn't available, the
other should be used.
>> Howard Bauchner: Janet, the WHO guidelines,
do they generally agree, either it's a class
effect and either of the two drugs that we've
been talking about are options?
>> Janet Diaz: Yeah. So when we presented
the data to the Guideline Development Panel,
yes, they agreed that either dexamethasone
or hydrocortisone as well giving the options
that those aren't available, then using an
equivalent dose of prednisone or methylprednisolone,
so a class effect.
>> Howard Bauchner: Now let's move to two
really difficult and complicated questions.
Todd, I'll start with you. And Janet mentioned
it, they're recommending against the use of
corticosteroids in mild illness. But if you
have a 70 year old whose breathing at 50,
may not have met the criteria that would have
gotten him or her into any of these studies,
but you think is going to deteriorate in the
next three or four days, and this actually
may be the majority of patients who end up
in the hospital. What do you do?
>> Todd Rice: Yeah. I think this is hard to
clinically implement these data and understand.
I think, you know, there's the signal from
the Recovery group that maybe dexamethasone
isn't that helpful in those patients which
doesn't bother me that much. What bothers
me more is this potential signal that maybe
it's [inaudible].
>> Howard Bauchner: Right.
>> Todd Rice: [Inaudible]. And then I'm left
with the question of in the Recovery trial
that was based off of whether or not you were
on oxygen, which at least in the United States
is not a very clear line as to how people
get put on oxygen. And so it leads me to the
question of there probably is a group that
these may not be the best treatment for and
how do I identify that group and how do we
avoid giving them to patients that potentially
could be harmed by them? And what you've proposed,
Howard, which I love the idea, the predictive
modeling of who's going to get worse, who
is at risk from becoming critically ill where
we know that they work? And I think there's
some work to do to truly understand where
that dividing line is and who the population
that, you know, it's pretty clear we absolutely
should give it and who the population is that
it's clear that we absolutely should not give
it.
>> Howard Bauchner: Janet, did the WHO guideline
committee wrestle with this because, as I
said, this is one of the great clinical questions.
It's easy if you know the person is, as I
said, breathing at 70, has huge O2 demands,
and is about to be intubated. They get steroids.
But it's this group on the way to that presentation.
And as critical care places, hospitals around
the country are less busy, they may be able
to pay more attention to these patients who
are getting worse. Did the guideline committee
wrestle with this group?
>> Janet Diaz: We did. And actually if you
read the guideline in table one there is a
little nuanced statement about that, that
it can't be so black and white, right. It
could be that someone has a saturation of
93% or 94%, but clinically they look like
they're on a downward scale, then the clinical
judgment should also be used to consider it.
And I think where we struggle is at the beginning
because at the beginning we only had the Recovery
data and they did the two subgroups, you know,
with oxygen or no oxygen and ventilation.
And so when we wrote our guidance there was
a discussion as do we use the same things
we recommended in patients on oxygen? We recommended
patients on ventilation? And that seemed difficult
for us to do because we didn't want to make
it based on the intervention that the patients
were receiving already because that could
be varied depending on the resources you have.
So we chose then to say we make the assumption
that most patients that would be put on oxygen
is because they have certain indications for
oxygen. And in our previous [inaudible] classification
system we have a severe classification which
is people who usually are on oxygen or have
some signs of respiratory distress and with
a critical classification so we chose to use
those classifications but then with a little
bit of a nuanced statement saying that it's
not so black and white because we don't know,
so clinical judgment in that gray period,
in that gray zone where you think someone
is on the way crashing but not yet there so.
>> Howard Bauchner: Jonathan, I mean you've
lived with this, literally lived this data
since we've had a lot of emails back and forth
including your quasi-vacation. You've lived
with this data for almost three months. Having
looked at the seven or eight clinical trials,
do you have a sense of how to differentiate
patients?
>> Jonathan Sterne: So the area we're talking
about has indeed been the hardest bits of
text to write and the bit where the authors
have argued most about the presentation of
the results. And the people who are interested,
I would encourage people to look at the supplementary
material where we have additional plots that
might help. So we do not have definitive results
here but we have a couple of hints. And the
first is that the trials recruited critically
ill patients but the definition of critically
ill varied between the trials. In three of
the trials we really only included patients
who were invasively mechanically ventilated.
They had a tube down their throat to help
them breathe. But in three of the trials there
were a few patients who were not invasively
mechanically ventilated -- sorry -- in four
of the trials there were a small group of
patients who were not invasively mechanically
ventilated when they were recruited to the
trial. And the [inaudible] it's only a signal
was the benefit was if anything greater in
the patients who were not invasively mechanically
ventilated in a randomization. And that tends
to, turns us in the direction that both Todd
and Janet have mentioned that it's not that
you need the intervention of a tube down to
your throat to benefit. It's that benefit
is in the sickest patients but not necessarily
waiting until there's tube in their throat.
The second piece of evidence that pulls in
the same direction is that the benefit of
corticosteroids appeared greater in patients
who didn't see [inaudible] by blood pressure,
they're the sickest patients. So it appeared
greater in the patients who were not so sick
that they needed those additional medications.
So Todd may want to comment further but those
were two pieces of evidence that really this
is about being sufficiently sick that you're
getting the problems resulting from the very
active immune system rather than waiting until
there is a particular intervention given.
>> Howard Bauchner: Todd, can you comment
on Jonathan's identification of the clinical
information within, in the trials because
I do think we're talking about what is likely
the majority of patients that come into the
hospital and potentially are in a critical
care unit.
>> Todd Rice: Yeah. I think he explained it
pretty well. I think that, you know, we talk
about should we give this when the patient's
on the ventilator, should we not give it when
the patient's not on the ventilator, and I
think the data are pretty, pretty suggestive
that the ventilator is not necessarily the
trigger for when these should be started.
And, you know, giving them to patients that
are pre-ventilator before they go on is also
beneficial. And we can argue about is it more
beneficial, is it less beneficial, I'm not
sure the data are that definitive as to more
or less but I think they're pretty definitive
that they're still beneficial.
[ Inaudible ]
Let me say this then he can comment. One of
the things that Hallie and I struggled with
a lot was what to say about the shock group.
>> Howard Bauchner: Ah. Could you explain
the shock group? People may not know what
you mean by the shock group.
>> Todd Rice: Yeah. The group that had low
blood pressure and were critically ill with
COVID but also had low blood pressure and/or
needed medicines to raise their blood pressure
to keep it in the normal range. And we struggled
with it because there are, as I think you
all know, there are data for patients that
have shock from an infection, septic shock,
that steroids may help that group. Forget
COVID. Steroids may help that group. And so
when the signal looked like it was less and
maybe not even present in those patients,
we looked at that pretty hard and talked about
it actually a lot among her and I. And I think
it's a hard signal to understand because in
many environments patients that were already
in shock, had low blood pressure may not be
eligible for randomization because their doctor
already thinks, "I'm giving this patient steroids
because I'm confident that it helps these
patients". And then in addition the REMAP
paper has a shock arm but less than half the
patients in that arm actually get shock, have
shock, and get the shock treatment. And so
I think that makes it hard to interpret those
data, too. Clinically I'll tell you I'm not
withholding the steroids in patients that
I have with COVID that are critically ill
that have low blood pressure. I'm giving it
to those patients also.
>> Howard Bauchner: Janet, do you want to
comment? I know that and I just want to point
out to the people who are watching or who
will eventually listen, Janet is a critical
care physician who trained in San Francisco.
And, Janet, you can depart from whatever the
WHO guidelines are and say what you would
do but I know you have to probably be pretty
careful about that. But can you just follow
up on what Todd just said because I know it's
a complicated issue besides who should get
it, the patients with shock or shock-like
syndrome?
>> Janet Diaz: Oh, yeah. I agree with Todd
actually. I would give them the corticosteroid.
I think we're, you know, based on the guidelines
it's also we would give based on the WHO to
recommend for patients with severe or critical
COVID-19 to use corticosteroids and that's
the recommendation. And that would include
someone with shock or without shock. So there's
no distinction being made at all in the guidance
and it wasn't really a topic of conversation.
And I do think from the literature, from the
non-COVID septic shock literature we helped
with the meta-analysis that were done in that,
you know, have been done for corticosteroids
that there is reasons to believe that it is
beneficial and suggestive of benefit in septic
shock as well as in potentially sepsis so
-- .
>> Howard Bauchner: Jonathan, go ahead.
>> Jonathan Sterne: [Inaudible] hopeful piece
of evidence that I should quickly mention
which is in the Recovery trial randomized
around 4,000 patients, a really, really large
number. And they were receiving oxygen and
many of them in really a variety of ways but
were not so sick that they were invasively
mechanically ventilated and mortality was
reduced in those patients. And we included
those data although they're not part of the
main perspective meta-analysis. We've included
that data in figure three in our paper. And
so I think it's really important to bear in
mind there are a much wider range of patients
in Recovery, and a very large number of patients
also provide evidence that if the patient
needed oxygen and in the context of UK healthcare
mortality was reduced by corticosteroids.
>> Howard Bauchner: Rob Gallop who's Director
of Scientific Review at JAMA, along with [Inaudible],
Rob always says, you know, people need to
understand the abstract is just a skeleton
of the paper and the paper just only is a
small part of entire study so I really oftentimes
when people talk to me about clinical trials
I often say, "You know, you actually have
to read the entire paper sometimes". And in
this case I think it really is worth reading
all of the meta-analysis, all the trials and
particularly look at the supplement. And I
want to go to one additional question. Derek
Angus and others have written in JAMA and
other journals. We've learned quite a bit
but now more complicated questions have come
up, the timing of drugs, combination drugs.
So now there's a literature around remdesivir.
I think it's mixed about its benefit. No definitive
data yet about convalescent plasma. But, Todd,
how do you see the combination of drugs working
now? With steroids is clearly the highest
quality evidence with the greatest gain. Remdesivir,
some gain. Plasma in the hearts of people,
a lot of gain, not a lot of high quality data
yet. So, Todd, how do you see the combination
of drugs working out?
>> Todd Rice: Yeah, I think you summarized
sort of the evidence level really well. I
don't think we know because I don't think
we have good data of these being used together.
Most of these patients in these steroid trials
were pre-remdesivir and they didn't get remdesivir
so understanding the combination of the two
I think is a little bit of a data-free zone.
But as I started at the beginning telling
you at least what I think is the mechanisms,
[inaudible] mechanisms that these treatments
would work through are different. So remdesivir
is an antiviral. Steroids I think decrease
the inflammatory reaction. And to me it makes
perfect sense that they should be synergistic
and work together. And I think that in my
practice I would use them together and I do
use them together. I think convalescent plasma
is a little bit of a fly in the ointment in
the fact that its mechanism of action is also
antiviral and so it and remdesivir may not
necessarily have combined effect when they're
used together and they may have similar mechanisms
and similar benefit if convalescent plasma's
strong beneficial dose. But I think both of
those are distinct from steroids. And I think
if you're using convalescent plasma, steroids
are likely to add benefit to that. And if
you're using remdesivir, steroids are likely
to add benefit to that also.
>> Howard Bauchern: Janet, before I go to
you to comment, one of the things that comes
up in the Q and A all the time when this question
comes up, Todd, is is there any reason to
think that steroids would adversely affect
the action of remdesivir or vice versa?
>> Todd Rice: Yeah. I think, like I said,
there's not a ton of data but from what I
know and from what I think we know from the
data, I don't have any reason to believe that
the two should have an antagonistic effect
and that they couldn't be used together.
>> Howard Bauchner: Janet, does the guideline
make any comment about combination therapy?
>> Janet Diaz: No. We do not make any comment
about combination therapy. We, in the ongoing
uncertainties part of the guideline we do
discuss this in the sense of with the strong
recommendation for these corticosteroids in
severe and critical disease. You know, now
let's say you're going to test immunomodulators,
right. So in some ways should they now be
tested against corticosteroids, right. And
so maybe a design of trials may need to be
adjusted after this. And then in regards to
other antivirals, these are direct antivirals,
again, I agree with Todd, I don't think there
would be any reason to think that they would
not be synergistic and since they're working,
you know, not being, what am I trying to say,
not being, you know, synergistic I guess in
treating COVID. I think the timing of antivirals
is the question as well, you know, with those
antivirals being perhaps earlier initiation
when the viral loads are very high to get
the best impact versus corticosteroids, what
we're seeing now with corticosteroids is not
necessarily the timing but actually the point
of the disease where you're having signs of
the inflammatory response or severity signs.
>> Howard Bauchner: Jonathan, I know you've
really focused on steroids but you've seen
the data from all of the trials. Do you have
a sense if there's an answer out there or
we need more information yet to really, to
begin to answer this question?
>> Jonathan Sterne: So I think it would be,
I think that the trials from now on, for all
that's speaking, are going to be assessing
a new therapy with corticosteroid compared
with the absence of that new therapy [inaudible]
corticosteroids. So what we're really going
to learn about from here on in, at least in
the critically ill patients, is about whether
adding something else to corticosteroid therapy
reduces mortality further than the corticosteroid
sort of already reduced it. And probably any
of the [inaudible] and indeed of the clinical
research community out there would at this
point say the same thing. I mean I'm not sure
what the [inaudible] number of patients with
COVID-19 to date is worldwide. It might be
25 million. We've seen that we can get definitive
results from randomized trials in only a few
thousand patients and for [inaudible] whether
a treatment or another treatment works is
not a matter of opinion. It is just the matter
of doing a randomized trial with sufficiently
many patients, finding the answer, and then
acting on the answer. It's not a political
issue whether drug A works or it doesn't work.
It is just the matter of doing the randomized
trials, finding out, and acting on the result.
So we simply need to randomize patients to
trial and then, and this is, of course, being
done to trials of remdesivir, to trials of
convalescent plasma, to trials of the new
immune therapies that are coming on, to therapies
that [inaudible] really important area is
whether we can find therapies that prevent
progression to severe illness and we need,
and we're going to need large numbers of patients
randomized in trials to do that. And then,
you know, I don't have a prior opinion and
the investigators of the Recovery trial, the
[inaudible] investigators, to me that before
they released their results they had 10,000
tweets telling them that they were evil people
for risking [inaudible] of steroids in these
sick patients because they were going to kill
them. And then after the results were released
they had 10,000 tweets people who said they
knew all along that corticosteroids were going
to work. Truth is if you don't know, do a
randomized trial and find out, and please
find out quickly because millions of patients
need the answers.
>> Howard Bauchner: I'd like to end there
because I think it's a call to the scientific
community and the clinical community and there
is always tension when you're taking care
of patients who are doing poorly about how
you can think about trying to put patients
into a clinical trial. I think clearly steroids
are now standard of care so everything must
be compared to steroids, but I think real
progress will be made by conducting clinical
trials and by the clinical trial community
cooperating like they've done in this case.
It's an extraordinary accomplishment and achievement.
So this is Howard Bauchner, Editor and Chief
of JAMA. This has been "Conversations with
Dr. Bauchner". Once again, I want to highlight
the WHO a guideline, Living Guidance they
call it, 2 September 2020 Corticosteroids
for COVID-19. It's being released simultaneously
with our publications. The editorial is by
Hallie Prescott and Todd Rice who's joined
me today, Corticosteroids in COVID-19 ARDS,
Evidence and Hope During the Pandemic. Then
a summary of the three trials. The effort
was led by Jonathan Sterne from the University
of Bristol, the WHO Rapid Evidence Appraisal
for COVID-19 Therapies, Association Between
Administration of Systemic Corticosteroids
and Mortality Among Critically Ill Patients
With COVID-19, a Meta-analysis. And then,
of course, my ultimate thanks to Janet Diaz
who's the head of the critical care within
the WHO Emergencies Program who has worked
tirelessly with many other people, both at
WHO and around the world, to get people to
cooperate, assimilate data, and be able to
really create a database that allows patients
to get better. I can't thank the three of
you enough, your co-investigators, and the
efforts, and thank you for bringing the papers
to JAMA. Take care.
>> Jonathan Sterne: Bye, everybody.
>> Howard Bauchner: Bye-bye, everybody. Please
stay healthy.
>> Janet Diaz: Bye. Thanks so much. See you.
>> Todd Rice: Thank you.
