Latest / European Society for Vascular Surgery / CREST 2 Trial: Changing Practice or Raising Questions? with B. Rantner & C. Hicks

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CREST 2 Trial: Changing Practice or Raising Questions? with B. Rantner & C. Hicks · European Society for Vascular Surgery

0:13
Hello and welcome to the ESVS podcast. I am Laurence
0:17
Bertrand. And I am Rosalinda D 'Amico. And today
0:20
we are discussing one of the most debated publications
0:22
in contemporary vascular medicine, the CREST
0:25
-2 trial and its implications for the management
0:28
of asymptomatic carotid disease. The trial has
0:31
generated intense discussion across vascular
0:33
surgery, neurology, radiology, and neuroradiology.
0:37
We're delighted to be joined by two outstanding
0:39
guests, both of whom have published prominent
0:42
commentaries on the CREST -2 trials. First, we
0:44
are welcoming back Dr. Rantner, Senior Vascular
0:47
Consultant at the Technical University of Munich
0:49
and Chair of both the current ESVS and DGG, that
0:52
is German -Austrian -Swiss Carotid Guideline
0:54
Writing Committees. We have previously recorded
0:57
one of our most popular podcasts comparing the
0:59
standing ESVS and SVS guidelines. We're very
1:02
happy to welcome you back, Dr. Rantner, once
1:03
more on the ESVS podcasts. Hello, everybody,
1:06
and thanks for having me again for an interesting
1:09
debate on this publication of PRESS2. And new
1:13
to our podcast, Dr. Caitlin Hicks, Associate
1:17
Professor of Surgery at the John Hopkins University
1:20
School of Medicine and Vice Chair of Research
1:23
for the Department of Surgery and part of the
1:27
Writing Committee of the ESVS and SVS Guideline.
1:30
Hello and welcome. Thank you for taking the time
1:33
to speak with us and share your valuable insights.
1:36
Thanks so much for having me. It's a pleasure
1:38
to be here. Before we go deeper, let me briefly
1:42
frame the study for our listeners. CRAS2 evaluated
1:46
patients with asymptomatic high -grade carotid
1:50
stenosis and compared carotid endarterectomy
1:52
plus best medical therapy versus best medical
1:55
therapy alone. And separately, carotid artery
1:59
stenting plus best medical therapy versus best
2:02
medical therapy alone. Importantly, carotid endarterectomy
2:06
and carotid stenting were not randomized direct
2:09
against each other, but each tested independently
2:12
against contemporary best medical therapy. Yes,
2:15
there were 155 participating centers that recruited
2:19
patients over 11 years, 2014 to 2025, with an
2:23
average follow -up of four years and just over
2:25
600 patients in each trial arm. That is 1 ,245
2:30
randomized between best medical therapy and stenting.
2:33
and 1 ,240 randomized between carotid endoterectomy
2:37
and best medical therapy. The main outcome of
2:40
the trial was clinical stroke rate, IPSI and
2:43
contralateral, up to four -year post -randomization,
2:47
and they found the standard patient to have significantly
2:50
better outcomes than their controlled medicated
2:53
group, 70 strokes versus 37, that is 2 .8 % versus
2:58
6%, with a p -value of 0 .02. The open surgery
3:03
trial, on the other hand, showed no significant
3:06
difference. That is 22 stroke or death within
3:10
the four years after surgery. So 3 .7 % versus
3:14
5 .3 % in its respective control group. Now,
3:21
we'd like to dig into the analysis of the results
3:24
and what clinical consequences might be, but
3:27
also, importantly, in the methods and how this
3:29
trial actually got to these results. The study
3:32
seems to have stirred up some heated discussions
3:33
in all those involved in the field of carotid
3:36
therapy. Here in Germany, the National Stroke
3:38
Association was quick to publish a recommendation
3:40
stating that stenting is now to be considered
3:43
of equal therapeutic value as operative repair.
3:46
I put the question first to you, Dr. Ratner.
3:48
Was this a surprise to you? And how are you experiencing
3:50
this in your center? Is there a debate on this?
3:53
Yes, as you already said, the CREST2 trial was
3:56
eagerly awaited and there was a lot of discussion.
3:59
I was quite surprised to see how much, because...
4:04
As you already mentioned, and this is very important,
4:07
carotid endarterectomy and carotid artresenting
4:09
were not randomized directly against each other.
4:13
So CRESS2 was not designed to allow a comparison
4:17
between the two treatment techniques. It was
4:20
only, if you like to say, designed to see if
4:23
either treatment technique was as or probably
4:26
even more effective in stroke prevention compared
4:28
to optimized medical therapy. Therefore, I can
4:33
only say that probably those who now think that
4:37
CAS plays a crucial role in asymptomatic patients
4:41
did either not fully understand or take that
4:45
much of attention off the crest. design or they
4:48
did not pay enough attention to ACS -T2 data.
4:52
Because in ACS -T2, which was a much larger trial,
4:57
including more than 3 ,200 individuals randomized
5:01
towards N -altractomercrotid autorescenting,
5:03
the equivalence of both treatment techniques
5:06
among asymptomatic patients was already demonstrated.
5:10
And this was published in 2021. To come back
5:13
to the question, is there heavy discussion in
5:15
our hospital? Fortunately not. Both techniques
5:18
are discussed and offered for asymptomatic patients,
5:22
but not only following the publication of CREST2.
5:26
Thank you for that. Dr. Hicks, what about you?
5:29
Before we dig into the details, can you tell
5:31
us... Is it being received with just as much
5:33
controversy in the U .S. as we are experiencing
5:35
here in Europe? Dr. Aburama's commentary in the
5:38
JVS also came relatively quickly after the publication,
5:41
stating that according to the American SVS, this
5:45
study does not provide sufficient evidence to
5:47
change the status quo. Have we interpreted his
5:49
statement correctly there? What is your opinion?
5:53
Yeah, I mean, I think it's a great question.
5:55
I will say that the study results have been met
5:57
with the... good deal amount of controversy.
5:59
When they were presented at the VIEF meeting
6:01
in November, it was probably the most attended
6:03
session I've ever seen at that meeting. And that's
6:06
a pretty well attended meeting. The interpretation
6:09
of the results, I think, varies by the specialty
6:12
that's doing the interpretation. So vascular
6:14
surgeons seem to interpret it one way, cardiologists,
6:17
interventional radiologists another way, and
6:19
neurointerventional radiologists yet another
6:21
way. That matters because stroke management really
6:24
is a multidisciplinary care process. And so even
6:26
the neurologists in our hospital had sort of
6:28
reached out after the study was published to
6:30
ask us to have a discussion on how to interpret
6:32
it. I think Dr. Abirama's commentary at the end
6:35
does say that the study doesn't provide sufficient
6:38
evidence to change the status quo. But if you
6:40
sort of read into the details, I think that that
6:42
needs to be interpreted with a little bit of
6:44
nuance. I mean, like all randomized controlled
6:46
trials, there are certain sort of constraints
6:48
and parameters associated with the trial. that
6:51
may not be reflective of real -world practice.
6:53
So when we're deciding sort of how to take those
6:55
trial results and interpret them into what we
6:57
do in everyday care, you have to be aware of
6:59
the details in order to make sure that you're
7:01
interpreting them correctly. So I think it provides
7:03
some insights in many ways, and I know we're
7:06
going to get into the details here, sort of around
7:08
the benefits of medical therapy, perhaps a role
7:10
for stenting that may be previously discounted
7:13
after the initial CREST -1 results. But I don't
7:16
think that the results of this study were enough
7:18
to fully change how we're taking care of asymptomatic
7:21
carotid artery stenosis. Now, we would like to
7:25
start with digging into the methods. This is
7:28
where many of the questions arise. Dr. Antner,
7:31
how big of a problem is that patients were not
7:34
randomized between stenting and operating and
7:37
might seem misleading to place both trials in
7:40
one study in this way? To clarify, patients were
7:43
really pre -selected for stenting or surgery
7:46
before randomization against past medical therapy.
7:50
Considering the body of evidence that exists
7:52
previously in which stenting repeatedly showed
7:56
worse results when randomized against surgery,
7:59
it would presumably have been difficult to truly
8:02
randomize many patients for which surgery was
8:05
a therapeutic option. What is your opinion? Patient
8:09
selection is a critical issue of CREST. And the
8:13
question why they decided to lead this totally
8:17
independent, in parallel study arms is not up
8:21
to my knowledge. I cannot answer. Probably Caitlin
8:23
has some background information why they decided
8:25
to design the study like that. It absolutely
8:28
seems worth mentioning that not only patient
8:31
selection, but also methodology was... special
8:35
in CRES2. So all patients were treated by transfemoral
8:39
access, which is meanwhile certainly not the
8:42
only standard of care that we have in carotid
8:44
artery stenting. So we can use atransradial or
8:47
direct access like in TCAR. I'm coming back again
8:52
to ACSD2. So it's not correct that literature
8:56
has proven the superiority of endartrectomy above.
9:02
carotid artery stenting amongst asymptomatic
9:04
patients, ACST2 has proven the equivalence. But
9:07
the necessity was that patients were treatable
9:11
by both treatment techniques. So ACST2 randomized
9:14
an individual either to endotracheotomy or to
9:17
carotid artery stenting. So comparable anatomy,
9:20
comparable aortic arch, comparable plaque morphology.
9:24
And if that was given... the treatment was either
9:29
way successful and safe. So yeah, patient selection
9:34
in CRES2 is a big issue. Caitlin, probably you
9:38
can add some information why they decided to
9:40
have these two independent arms. in parallel.
9:46
Yeah, I think you make some good points there,
9:48
Dr. Reiter. And I think the reason why this trial
9:51
was initially designed this way was that ACST2
9:53
was already underway and enrolling when CREST2
9:56
started. And so they didn't need to replicate
9:57
that study. And secondly, sort of the big impetus
10:01
behind CREST2 was that medical therapy has improved
10:04
since sort of the historical broadened revascularization
10:07
trials that we all rely on to inform our practice.
10:10
And so the question behind this study was, is
10:13
medical therapy so much improved that it is now
10:16
equivalent to carotid revascularization in patients
10:18
with asymptomatic disease. And so the study was
10:21
designed in this way, not to compare the interventional
10:24
arms, but really to compare and to focus on the
10:27
best medical therapy arm versus interventions.
10:29
And it was ultimately designed in sort of this
10:31
two parallel study design, I do believe because
10:34
of power. And so there was a three -way study
10:37
design, you needed a lot more power in events
10:39
between the groups in order to get statistical
10:40
significance. Whereas in this design, one or
10:44
both of those analyses could become significant
10:46
on their own. And so that was the thought process
10:49
behind it. And I think that it makes sense sort
10:52
of for how it was designed, if you understand
10:54
those reasons behind it. But the problem with
10:56
the design is exactly what you said, is that
10:58
people are thinking about this as comparing across
11:01
the two parallel studies. So some things that
11:04
I have heard is that... broad and scenting is
11:06
better than CEA. Well, it wasn't meant to show
11:09
that. And in fact, it doesn't show that. And
11:10
so I think we have to just be very careful about
11:12
the interpretation of the study within the design
11:15
itself. Thank you for that. Dr. Hicks, I'd like
11:20
to continue with you and ask about the differences
11:22
in the inclusion criteria, or rather the exclusion
11:24
criteria. The CREST2 study publishes a rather
11:27
long list of limitations for inclusion to the
11:29
stent arm, most of which were not exclusion factors
11:32
for the surgical therapy arm. Now, this might
11:35
have been necessary to... do that way because
11:38
of previous existing evidence. I'll list some
11:40
of the exclusions I'm talking about. These include
11:43
stenotic lesions over three millimeter thickness,
11:45
over three centimeter in length, non -contiguous
11:47
lesions, internal carotid vessels under four
11:50
millimeters or over nine millimeters. tortuosity
11:53
in the carotid or access vessels, severe arch
11:56
atherosclerosis, and also, I quote, even more
11:59
careful evaluation of the calcifications in patients
12:01
over 70 years old. The question is, first of
12:04
all, is that a fair way to look at all these
12:06
lesions? And secondly, does that mean that it's
12:10
not very representative of the lesions that are
12:12
really seen? What's your opinion, Dr. Hicks?
12:14
How problematic is the difference in exclusion
12:16
criteria between the two trial arms? Yeah, this
12:20
is, I think, a really important point. So I think
12:23
the trial was designed this way because of reason
12:27
for equipoise, right? So if you have a patient
12:29
and they're going to be randomized to receive
12:30
carotid stenting, and they're a poor candidate
12:32
for carotid artery stenting, you don't want that
12:35
to happen. And so they sort of put all these
12:36
constraints in the carotid stenting group to
12:38
make sure it was appropriate that a patient be
12:40
randomized in that way. What ended up really
12:42
happening is that most physicians were only able
12:45
to randomize patients into either the medical
12:47
therapy versus CA arm. or the medical therapy
12:50
versus stenting arm. There was only one or two
12:52
physicians in the entire study that were able
12:54
to randomize into both. So this ended up actually
12:57
being biased by physicians' individual practices.
13:00
But in the end of the day, what we got here was
13:02
sort of an optimal stenting group, whereas there
13:04
were much fewer exclusion criterias in the endarterectomy
13:07
group. And so I think on the one hand, you could
13:09
argue that these are patients that were truly
13:11
eligible for carotid stenting, right? They are
13:14
optimal. candidates. And therefore, now we can
13:16
look at how medical therapy versus stenting does
13:18
in this optimal candidate group. And so you've
13:21
interpreted it that way. On the other hand, it
13:23
probably isn't representative of what's happening
13:25
in the real world. Patients come in, and if physicians
13:28
only can perform stenting, they're going to get
13:30
a stent if that person thinks they should get
13:33
a carotid revascularization. And so it's probably
13:34
a little bit biased or unfair and represents
13:37
maybe better than expected outcomes in the carotid
13:40
stenting group compared to what we would see
13:42
in real world evidence. Not only patient selection
13:46
was stringent, but also surgeon and interventional
13:51
selection was defined. All candidates had to
13:55
have combined stroke and death rates of less
13:58
than 3 % in asymptomatic patients. Surgeon needed
14:02
to provide procedural reports in at least 50
14:05
consecutive cases, so 90 % of applicants were
14:08
accepted. while interventionalists needed to
14:11
have completed 25 cases in the last five years
14:15
and 50 in total. So only 50 % of the candidates
14:19
were accepted. Now, Dr. Rentner, in your opinion,
14:23
what would you say to those who claim the study
14:25
compares the average vascular surgeon to a group
14:29
of super users in carotid stenting? So the question
14:35
about the generalizability of RCT data in terms
14:38
of patient recruitment and operator performance
14:41
is always an issue. The request to treat below
14:46
an overall stroke and death rate of 3 % is, however,
14:49
in my mind, absolutely reasonable and necessary
14:53
in the context of asymptomatic carotid artery
14:56
stenosis. So this is overall recommended. We
15:00
will also stick to that in the ESVS guideline
15:03
update. This is requested as a maximum 30 -day
15:07
complication rate, irrespective of the treatment
15:10
technique. So I'm not sure if there is really
15:13
a comparison between an average vascular surgeon
15:16
and a super user, as you call it, in carotid
15:20
artery stenting. As we already heard, it was
15:23
a lot about patient selection in CRAS -2, probably
15:26
more than about technical skills. My next question
15:30
goes back slightly to the inclusion criteria.
15:32
And I would like to bring our attention to the
15:34
fact that unlike current European guidelines,
15:36
there was no need for high -risk features to
15:38
allow patient inclusion. Dr. Ratner, is it fair
15:41
to deduce, therefore, that the study population,
15:43
therefore, does not represent the patient population
15:45
that in Europe, at least, would be considered
15:47
appropriate for surgical treatment? And what
15:51
is the consequence of that disparity when looking
15:52
at the results claiming surgery to potentially
15:55
be ineffective? two was the first trial that
16:01
chose 70 % for asymptomatic patients. You might
16:05
be aware that the so far available literature
16:07
included individuals with 60 % asymptomatic synopsis,
16:11
which is different also to the symptomatic group
16:13
where we start at the 50%. To my knowledge...
16:17
Unfortunately, so far, no RCT ever included a
16:21
more detailed plaque morphology diagnostic to
16:24
indicate revascularization or not. So this is
16:29
certainly not common practice, but the CRESS
16:35
-2 study group published very recently data of
16:40
the plug composition from the first 500 included
16:44
individuals, where they had a closer look to
16:47
the vulnerability of the plugs only done by ultrasound.
16:53
So they did not add any advanced plug imaging,
16:58
for example, by MRI or CT scans. But anyway,
17:02
probably they can draw some attentions also from
17:06
the pluck morphologies and thereby allow a better
17:11
understanding who of asymptomatic patients especially
17:16
benefits from best medical therapy and who will
17:19
not. So the qualitative, as you already mentioned,
17:23
characteristics of stenosis and the stenosis
17:26
length was an issue in CAST patients in CREST2,
17:31
but it was not in the surgical group. Dr. Hicks,
17:37
what's your personal opinion on the matter? Can
17:39
we ask you? Yeah, I think the patients that were
17:43
included in PRESS -2 represent the patients that
17:46
are receiving carotid revascularization for asymptomatic
17:49
disease in the U .S. So I know in Europe, it's
17:53
much stricter and sort of there's a narrower
17:54
band of patients that are treated. In the U .S.,
17:56
it is very common to treat patients regardless
17:59
of whether or not they don't have high -risk
18:01
features. I do think that most of us that do
18:04
a lot of carotid surgery, feel pretty strongly
18:06
that not all asymptomatic carotid disease is
18:10
the same. And there are certainly some patients
18:12
that will likely benefit based on their plaque
18:14
components and some that will not. What those
18:16
exactly are, however, though, I think still remains
18:18
quite to be determined. And hopefully CREST -2
18:20
can continue to shed light on that as more data
18:22
comes out. As Dr. Ratner mentioned, there's great
18:25
ultrasound data. So I know some of the first
18:27
data has come out, but we had to send in the
18:29
ultrasound images, the actual images for every
18:31
patient who was involved in this trial. And then
18:33
there are also a number of patients that were
18:35
enrolled in a sub -study where MRI was obtained.
18:37
And so hopefully as those data sort of come forth,
18:39
we'll have a better understanding of who may
18:41
and may not benefit to a greater degree of undergoing
18:45
some sort of revascularization decision strategy
18:47
for asymptomatic chronic disease. Thank you for
18:52
your opinion on that. That's very valuable. Next,
18:54
we'd like to talk about crossover rates. There
18:57
is an important protocol publication that came
19:00
out in 2017 in the International Journal for
19:02
Stroke in which the plan for CREST2 was outlined
19:05
in detail. Now, in it, they outlined power calculations
19:08
allowing for an anticipated 5 % crossover rate
19:12
between intention to treat and post -randomization
19:15
crossover to an alternative treatment arm. In
19:18
actual fact, while none of the patients randomized
19:20
to surgery crossed over, 7 % planned for stenting
19:23
weren't. That's 43 patients. And in both trial
19:27
arms, 17 % and 18 % of the best medical therapy
19:30
patients were in fact treated invasively. The
19:33
highest crossover went from the control group
19:35
in the open surgical trial, where 94 % of the
19:38
623 planned conservative treatment ended up receiving
19:41
open surgery, actually. What's your analysis
19:45
of this issue, Dr. Hickson? How are we to use
19:47
this information when interpreting the study?
19:49
There's always a level of crossover, and that
19:51
is to be expected. It's correct to use intention
19:55
to treat analysis. Is it simply a consequence
19:57
of randomized controlled trials that we are to
19:59
accept? How much does this weaken the intention
20:02
to treat analysis, in your opinion? Yeah, I think
20:06
this is a point that is brought up by a number
20:08
of people who sort of have really read this study
20:10
closely. At the end of the day, an intention
20:12
to treat analysis is exactly that, right? Patients
20:14
were randomized into one arm, and then they are
20:16
analyzed into the arm that they were supposed
20:19
to receive. And that's sort of supposed to mimic
20:22
what we do in real life. The problem, I think,
20:24
here becomes in these sort of high crossover
20:27
situations, especially when there are very few
20:30
event rates. So in this study, there was less
20:32
than 40 in the group with the highest number
20:35
of events. The problem, because if you have crossovers
20:38
of 17 and 18, percent of patients, it starts
20:42
to get very, very muddy about whether or not
20:45
the events that happened to happen because they
20:47
were on best medical therapy and then had a stroke
20:49
or whether they had a event because they had
20:51
a surgical revascularization, but they were supposed
20:54
to be getting best medical therapy. And that
20:56
sort of, I think, does cause some confusion here.
21:00
Ultimately, we'll need to see the protocol analysis
21:02
to see whether or not this actually had a significant
21:05
impact on the interpretation of the study results.
21:07
And I have not yet seen that. For now, we are
21:11
supposed to interpret this as an intention -to
21:12
-treat concept, and that is the way that randomized
21:15
controlled trials are meant to be analyzed. Dr.
21:19
Anton, on the topic of follow -up, we know that
21:22
recruitment stopped in 2023, yet the paper was
21:26
published roughly one year later, rather than
21:29
after all patients had the opportunity to complete
21:31
the intended four -year follow -up. In your opinion,
21:35
does the difference in follow -up duration, particularly
21:38
the slightly shorter follow -up in the carotid
21:41
stenting trial, influence how do you interpret
21:45
the comparative results? So, follow -up duration
21:50
addresses long -term durability of a procedure
21:53
and provides a net benefit for interventions
21:57
compared to, in this context, conservative management
22:00
in a disease. In the context of carotid artery
22:03
disease, different follow -up periods were covered
22:06
in the last years. The very recently published
22:09
ECST2 trial, for example, published two -year
22:13
preliminary results. Even though they called
22:16
it interim, results were still interpreted and
22:20
the trial was very critically discussed. CRESS2
22:24
now reported a quite uncommon safety endpoint
22:27
of 44 days and an efficacy endpoint after four
22:31
years. The problem in this context might, in
22:35
my mind, be the rather small number of individuals,
22:38
of participants, and small number of events in
22:42
both groups that led to this very similar and,
22:44
in the end, still different outcome analysis
22:47
as was already depicted by you after the four
22:50
years leading to a... net benefit for carotid
22:54
artery stenting, but not for endartrectomy. So
22:57
the less individuals and the smaller number of
23:01
endpoints, the more important is the long -term
23:05
follow -up. We compared those results with the
23:08
ACST2 data. And if you merge the graphs, it's...
23:13
almost identical and probably the 5 - and 10
23:16
-year outcome analysis of CRAS2 will be equivalent
23:21
to the ACST2 results showing a net benefit for
23:24
both revascularization strategies. All right.
23:29
While we have concentrated on some of the important
23:33
limitations of the paper, we also want to take
23:35
the chance to highlight some valuable strengths.
23:39
In particular, one of the most widely praised
23:41
aspects of CREST2 is the exceptionally high standard
23:45
of best medical therapy, including evolving lipid
23:49
targets, access to therapies such as alirocumab,
23:53
evolucimab, and structured lifestyle coaching,
23:56
derived by FON. The authors have also published
24:00
important comparative tables showing that intervention
24:03
arm in both trials also received the benefits
24:07
of this best medical protocol and their blood
24:10
pressure and LDL targets were stringently adhered
24:14
in all the four groups. Dr. Hicks and Dr. Antner,
24:18
I put the question to both of you. What, in your
24:21
opinion, are the most important takeaway of the
24:25
success of the conservative therapy? So I think
24:31
it was more than necessary to have a contemporary
24:34
optimized medical therapy trial that was able
24:38
to show that with improved and very intense medication,
24:43
risk parameters can dramatically be reduced and
24:48
can be controlled very well in the carotid population.
24:52
And this leads to way better results in the...
24:57
natural course also to better outcomes for revascularization
25:01
strategies. I think that's a great point. It
25:06
wasn't that just this medical therapy was applied
25:09
to the medical therapy group. It was applied
25:11
to both groups. And so hopefully there was a
25:14
benefit that we saw sort of in both those groups.
25:16
I think it speaks to the fact that medical therapy
25:18
does quite well if delivered properly. And I
25:22
think that we'll get to that conversation. you
25:25
know, patients do need to be followed for their
25:27
blood pressure. You do need to be checking their
25:29
LDL levels. It is important to do lifestyle coaching
25:31
around healthy behaviors. And PRESS -2 was able
25:34
to achieve all of those things. And so I think
25:36
the take -home that I had from this trial is
25:39
that, you know, all said and done, if a patient
25:41
is not a great candidate for coronary vascularization,
25:44
but we can optimize them on medical therapy,
25:46
they'll probably do pretty well, at least in
25:48
the short term, as long as we can get them. to
25:51
using that optical medical therapy. And hopefully
25:53
we can use some of those concepts as we counsel
25:55
patients on the importance of adhering to the
25:58
medications that we prescribe. Yeah, I think
26:01
that brings us nicely to my next question, where
26:03
really the question is, how realistic is it to
26:05
achieve that what CREST 2 is presenting to us?
26:09
There has been some critique in the aforementioned
26:11
commentary by Abogama and co., for example, that
26:14
places doubt on the feasibility on the level
26:16
of support and thus compliance achieved in CREST
26:18
2 for medication. Dr. Ratner, how would you respond
26:20
to that? And how should clinicians reconcile
26:23
this with their own clinical setting? There were
26:27
some hopeful leaves in Caitlin's comment. So
26:32
now that we are aware that the patients need
26:36
strict control and very intense guidance to stick
26:42
to the medication they should be on, I really
26:44
doubt that... that our daily routine can provide
26:49
such an intensive and well -conducted best medical
26:53
therapy to everybody, especially in Germany where
26:56
the discussion about hospital reorganization,
27:01
the question is still unanswered who will be
27:06
the relevant caretakers of those patients, who
27:09
will see those patients in the future. and who
27:12
is really interested in guiding them as intensely
27:16
and as properly as they should be guided, carotid
27:20
patients are still not as valuably treated as
27:23
our cardiac patients, for example. Therefore,
27:26
one of my... take -home messages from CRESS2
27:30
is still that there is a strong call for revascularization
27:34
amongst asymptomatic patients because even under
27:38
optimized conservative conditions, the natural
27:41
stroke rate, as I already mentioned, is high.
27:45
It was 1 .3 and 1 .7 percent per year. So we
27:49
are not able to prevent all the strokes we need
27:52
to prevent. Another very valuable analysis the
27:58
CREST -2 discussion section provides is the so
28:01
-called tipping point analysis. That is, they
28:04
have calculated how many more or less strokes
28:07
needed to have happened to gain or lose significance
28:10
in each trial arm. They showed that the significance
28:14
showing advantage for stenting versus medication
28:17
was lost if there were as little as three more
28:22
strokes in the CAS arm and four less strokes
28:25
in the BMT arm. In the surgical trial, seven
28:30
less strokes in the surgical arm versus six more
28:33
strokes in its comparative medication arm would
28:36
be needed to find a significant difference. Dr.
28:40
Hicks, how much stock do you put in this analysis?
28:43
Intuitively, I would say that those sounds like
28:46
small numbers. Is that a fair assessment? And
28:50
how would you put it into perspective? Yeah,
28:53
I think the tipping point analysis for the CRUST
28:55
-2 paper was actually a really important component.
28:58
So, you know, we historically put a lot of stock
29:02
into statistical significance defined by a p
29:04
-value. that's determined by a power calculation,
29:08
et cetera. But in this specific study, the statistical
29:11
significance that was found in carotid stenting,
29:13
but not in carotid endarterectomy, is very, very
29:17
tenuous. And you can see this in this tipping
29:19
point analysis. Literally less than 10 events
29:21
sort of going in either direction would have
29:24
swung the analysis from being significant to
29:26
not significant or vice versa. And I think that
29:29
sort of speaks to just sort of how... small the
29:33
ultimate impact you're having on patients and
29:36
probably the natural history of the disease.
29:39
I think as we follow patients longer term, this
29:41
will start to spread out. And when you look at
29:43
the Kaplan -Meier curves in the CREST -2 paper
29:45
that show event rates over time in the medical
29:47
therapy arms, both of them, and then the scenting
29:49
group and the endarterectomy group, that is very
29:51
clear visually. There's a clear separation after
29:54
two years that patients who received revascularization
29:56
at least look visually to be doing better than
29:59
those that received medical therapy. But I think
30:02
what this analysis goes to show us is that when
30:04
you do the statistical analysis, it's actually
30:07
quite a tenuous finding, and we ultimately need
30:09
more events in order to say that definitively.
30:15
Thank you for that. I'd like to dive a little
30:17
bit deeper into the results. One of the main
30:20
outcomes reported is the periprocedural stroke
30:22
or death 44 days after randomization. So that's
30:25
30 days postoperative with a grace period of
30:27
two weeks given between randomization and performing
30:29
the interventions. While the stenting trial had
30:32
seven strokes and one death peri -interventionally,
30:35
the best medical therapy for that trial had no
30:37
events. In the surgical arm, the best medical
30:39
therapy group had three strokes within 44 days
30:42
after randomization. and nine strokes in the
30:46
surgical group. Dr. Ratner, what's your take
30:48
-home message from this outcome? It seems like
30:49
there was hardly a difference in the stenting
30:51
and surgery trials, and actually one patient
30:53
sadly died in the stenting group. Yeah, this
30:56
brings us back to the beginning of the discussion
30:59
about equivalence and comparability of treatment
31:02
techniques. So if we just look at the safety
31:06
outcome, numbers are absolutely comparable between
31:09
endotrectomy and carotid artery stenting, as
31:11
you just mentioned. So if we would like to compare
31:16
the techniques, we would see that the immediate
31:20
efficacy and stroke prevention potential was
31:23
equivalent. But again, this was not the intent
31:27
of CREST2. Up to now, all stroke results reported
31:34
there have been overall clinical strokes, both
31:37
ipsi and contralateral. In the over 44 days result,
31:42
the study specifies ipsilateral stroke rates.
31:45
The stenting trial shows a reduction from 1 .7
31:50
% annual ipsilateral stroke rate under medication
31:54
alone to 0 .4 % annually after stenting. There
31:59
was a similar reduction of 1 .3 % annually under
32:03
medication alone to 0 .5 % annually after surgery.
32:08
Dr. Hicks, what is your take on message from
32:11
this outcome? And what would you like to bring
32:14
our attention to? Yes, in terms of a long -term
32:17
sort of stroke reduction with carotid revascularization
32:20
or medical therapy, I think these results show
32:23
you that after a carotid revascularization procedure,
32:26
be it stenting or endarterectomy, the risk of
32:28
stroke annually thereafter is pretty low in patients,
32:31
right? Around 0 .4, 0 .5%. The thing of note
32:35
in these results is that the patients in the
32:38
medical therapy arm who were in the stenting
32:40
trial did worse than the patients who were in
32:42
the medical therapy arm in the endarterectomy
32:45
trial. And that's sort of one of the risks you
32:46
have of having two medical therapy arms that
32:49
are enrolled separately. And so whether or not
32:52
this just reflects a random chance that the patients
32:55
just did a little bit worse or whether patients
32:56
that were referred for randomization in the stenting
32:59
trial were higher risk than those who were referred
33:02
for endarterectomy. We don't really know. But
33:04
certainly when you're talking on the order of
33:07
tens of events, just tip the analysis one way
33:10
or another from a statistical significance standpoint,
33:13
the fact that the patients in the medical arm
33:15
in the stenting group did worse definitely drove
33:18
that statistical endpoint. And so I think it's
33:20
important to sort of note that those medical
33:23
therapy patients didn't do quite the same. They
33:25
did relatively similar. We can summarize that
33:27
risk sort of in the one and a half percent range
33:30
per year. that difference was large enough likely
33:33
to drive the non -significance in the endodirectomy
33:36
trial. Before we move away from results discussion,
33:41
we would like to draw our attention to figure
33:44
three, in which a great number of sub -analyses
33:47
are reported within the study. I put the question
33:50
to both of you. Which of these sub -analyses
33:53
would you like to draw our attention to? Is this
33:55
potentially a map to who in fact really should
33:58
be standard and not operated in real life patient
34:02
population today? I think the sub -analysis,
34:07
you have to take it with a grain of salt in this
34:09
study. I mean, even in the main analysis, we
34:11
didn't have enough event rates to reach statistical
34:13
significance for some of the endpoints. And so
34:15
when you start divvying this out into a bunch
34:17
of different subgroup analyses, while I understand
34:20
sort of the rationale for doing so. You can't
34:22
take much stock in the statistical or non -statistical
34:25
nature of any of these. And so I think it's hard
34:27
to make conclusions in most of those sub -analyses.
34:30
They have to do them because they were sort of
34:31
based on things that we know from past trials,
34:33
but I'm not sure that I would take much home
34:35
from those. Moving on, and Dr. Renner, you talked
34:39
about this a little bit in the beginning of the
34:40
podcast. I'd like to ask about TCAR, an important
34:43
player that's not included in CREST2 at all and
34:45
might change the game for asymptomatic carotids
34:47
in the foreseeable future. Dr. Hicks, we see
34:50
from the VQI data that TCAR is widely in use
34:53
in the United States and generally outperforms
34:55
transfemoral carotid stenting year after year.
34:58
What's your opinion on the matter? Yeah, TCAR
35:00
is sort of the big black box around CREST2, at
35:03
least within the United States, because it has
35:05
taken up a huge amount of market share in both
35:08
the asymptomatic and symptomatic patients. I
35:10
was one of the enrollers in CREST2, and I sat
35:13
on some steering committees when they were actually
35:14
talking about making a trial amendment to ultimately
35:17
include TCAR as a potential revascularization
35:19
strategy. And at the end of the day, that didn't
35:21
happen because they couldn't add a third arm
35:24
where they were comparing TCAR versus medical
35:26
therapy. It was too late in the game. And the
35:29
investigators and the NIH couldn't decide whether
35:31
TCAR belonged in the surgical group or in the
35:34
stenting group, because ultimately you're doing
35:36
a carotid cut down, so that's some sort of surgery,
35:38
but you're placing a stent and you're putting
35:40
the patient on dual antiplatelet therapy, which
35:42
is more like stenting. And so at the end of the
35:45
day, the decision was made to not include that
35:46
technology as a revascularization option. I think
35:50
for a lot of us that do a lot of TCAR, we probably
35:52
would put it more in the stenting group than
35:54
in the... the carotid endarterectomy group and
35:57
what the interpretation in the U .S. has been
35:59
is that, oh, extenting is great for patients
36:01
with asymptomatic carotid disease. That also
36:03
means that TPAR is great for those patients as
36:05
well. I don't know that you can truly make that
36:08
jump. I mean, it wasn't tested in this trial,
36:10
but that's certainly what's happening in sort
36:12
of chlorophyll vascular surgery here in the U
36:14
.S. And it does track at least following the
36:17
best with quality initiative data, right? TCAR
36:19
always does better than transferable stenting
36:21
within that cohort. But that cohort is a little
36:24
bit self -selected and it doesn't sort of represent
36:27
transferable stenting being done by a lot of
36:29
other specialties. And so I think there's still
36:31
very much a question around the use of TCAR.
36:33
I think it's a great technology for those who
36:35
have access to it. And I think at the end of
36:37
the day, what procedure we choose for which patient
36:40
ultimately depends on sort of the indications
36:42
for why the patient is receiving surgery. and
36:45
the anatomic and medical risk factors that they
36:47
have that will ultimately sway you as a surgeon
36:50
or an interventionalist to perform one surgery
36:52
or revascularization strategy over another. Thank
36:56
you for valuable insight. What would you say
37:00
is the European perspective on this, Dr. Ratner?
37:01
Is CREST2 going to be relevant in the introduction
37:04
of TCAR in the European space in any way, at
37:06
least in the conversation around that? So TCAR
37:11
is in every... In every conversation we are having
37:16
also in Europe about carotid revascularization.
37:20
But unfortunately, we don't have access to it.
37:24
There is no randomized evidence available so
37:27
far. I'm not sure if there ever will be randomized
37:29
evidence available. And we are not familiar with
37:33
the VQI registry data. We don't know a lot about
37:38
the trustability, if that's okay to say, of these
37:41
registry data where all the knowledge of TCAR
37:44
comes from. So also in the context of guidelines,
37:48
it's very difficult to recommend TCAR in Europe
37:52
because we cannot recommend a technology that
37:55
is not available for the majority of caretakers
37:59
in Europe. Thank you for those insights. Now,
38:02
I have a question for both of you. We have touched
38:05
the most important aspect of methodology and
38:09
results of this study. Would you like to draw
38:12
our attention to other specific aspects? I think
38:15
the big take -home for Quest 2 is not sort of
38:17
these very specific nuances of, you know, these
38:19
many strokes happened in three versus seven other
38:21
patients, etc. I think it's around sort of choosing
38:25
patients properly. for carotid intervention or
38:28
not. You know, can you get them on medical therapy?
38:30
Should they be receiving a revascularization
38:32
therapy? Do they have the longevity to see benefit
38:34
in that? And then if you're going to choose a
38:37
revascularization strategy, which one is best?
38:39
And that probably comes to your own personal
38:41
skill set if you're the one doing the procedure
38:43
and the patient's sort of tolerance and anatomic
38:46
criteria, as we've sort of talked about in the
38:48
nuances of patients that were enrolled in one
38:50
arm versus another. And so my take home of PRESS
38:53
-2 is really that We need to sort of be thinking
38:56
about all of these concepts as we counsel patients
38:58
on the risks and benefits of carotid revascularization
39:01
and which carotid revascularization they should
39:03
have, and not so much that one is better than
39:06
another and this is always the way that we should
39:08
go. For me, it was really good to see that we
39:11
should think about revascularization at all in
39:14
asymptomatic patients, as I said earlier. So
39:16
the suggested exclusively conservative management
39:20
for asymptomatic patients is, in my mind, not
39:22
justified. CREST showed that best medical therapy
39:27
is absolutely necessary and beneficial for everybody,
39:30
irrespective if he is revascularized or not.
39:34
And if we additionally stick to the high -risk
39:37
plug criteria, then I think we have valuable
39:41
opportunities in selecting patients, irrespective
39:45
of the treatment technique, to revascularize
39:48
asymptomatic patients additionally to optimize
39:51
their risk factors. So now for our last question,
39:56
this is one for both of you again. I'd like to
39:58
ask each of you to briefly, based on the CREST
40:00
-2 as it stands today, what should clinicians
40:02
do differently, if anything, in their practice
40:04
right now? I fully agree with Dr. Aburama. There
40:09
is no need to change our clinical practice after
40:13
the publication of CRESS2 and we will not change
40:15
the recommendations. I can probably give you
40:19
a sneak preview for the ESVS guideline update.
40:22
We will not dramatically change the recommendations
40:25
towards revascularization of asymptomatic individuals.
40:28
Patient selection is essential and the quality
40:31
of revascularization needs to be good, you need
40:34
to prove that you're able to treat those patients
40:37
with an accepted stroke or complication rate
40:41
below 3%. That's more or less it. Yeah, I think
40:46
the other thing it gives me, you know, when I'm
40:48
counseling patients on whether or not to get
40:50
surgery for asymptomatic heart disease, what
40:53
they really want to know is what is their risk
40:54
if they don't have surgery. And so what CREST
40:57
2 gives us is some real numbers around that and
40:59
on the assumption that they're doing best medical
41:01
therapy. And so I think that it's helpful from
41:03
the stance that it can say, you know, today,
41:06
if you do these four things, this will be your
41:08
risk of a stroke in the next year versus this
41:12
would be potentially your risk of stroke with
41:14
carotid revascularization. But at the end of
41:16
the day, it doesn't really move the needle on
41:18
whether or not I offer revascularization at all.
41:20
I think it maybe just sort of enhances or gives
41:23
more details to the counseling. Amazing. Dr.
41:28
Ratner, Dr. Hicks, we want to thank you very
41:30
much for joining us and for engaging so openly
41:32
in this discussion. It's been a privilege to
41:35
hear you and your thoughtful insights on these
41:38
topics. Thanks. Thanks also, Caitlin, for sharing
41:43
the discussion. It's always good to have somebody
41:46
from, as I meanwhile call it, from Crest 2 land.
41:49
You have much more insights than we Europeans
41:51
have over here. So it was very valuable also
41:54
for me to discuss these Crest data with you.
41:57
I think it's so fun to sort of talk about the
41:59
different perspectives from a European versus
42:01
sort of... North American viewpoint, because
42:04
I think a lot of times we think that we think
42:06
about these things very differently. And I think
42:08
from this conversation, it's come out that we
42:10
think about these things very similarly, and
42:12
that's been very, very helpful. And thank you
42:17
for listening to the ESVS podcast. We look forward
42:21
to welcoming you again next time. Bye.