Research Talk - Adam de Havenon - Yale - YNHH

October 27, 2021

ID7088

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00:00Thanks daddy.
00:03I'll try to keep it short and sweet now.
00:05Hang on, I'm the last one I.
00:08Uhm, wanna just talk quickly about
00:12a study that I'm proposing to stroke
00:16net with several collaborators,
00:18which I'm sure many of you know, sappy.
00:22And David Ron, who is a neuroradiologist
00:28at wash U that many of you may not know.
00:31And and Jordan,
00:33of course familiar to many of you.
00:36Essentially it is an ancillary
00:40study proposal to Captiva Captiva,
00:43which has been funded and doctor
00:47Broderick described it earlier today.
00:50But I do wanna touch on just
00:52a couple points quickly.
00:55Come and chat.
00:56He's talked a little bit about intracranial
00:59athero which I'll call eye casts.
01:02But one thing that I think we don't
01:06discuss enough is that overall worldwide
01:10it is the most common cause of stroke.
01:13So taking into account its prevalence
01:17and the mechanism being more common.
01:22In Asian and patients of other
01:27other underrepresented groups,
01:29it gets you to the most common cause
01:34and chatty showed you great data
01:37from Chicago that really we expect a
01:42recurrence rate of about 20% per year.
01:47If you take carotid stenosis as a comparator.
01:52We have excellent medical and
01:54surgical treatment,
01:55so with some treatment I can expect
01:59a recurrence rate of around 2 to
02:034% per year for carotid disease.
02:05So why did the treatments that
02:08work so well for carotid disease
02:11not work as well for eikaas,
02:14and why do we still have such
02:16a high rate of recurrence?
02:18Well, one thing to take into account is that.
02:22When?
02:23Mens was funding multiple
02:26trials and six trials.
02:30Looking at carotid disease.
02:33Come and you could expand this further out,
02:37but I think a lot of the
02:39advances in terms of medications.
02:42Were already apparent by 2005.
02:47They had only funded one study
02:50for intracranial athero an
02:52and subsequent to that.
02:54Of course we had Sampras
02:56and Captiva has been funded,
02:57but I would argue that a
03:01disproportionate amount of funding
03:03has gone to study carotid disease,
03:07and I think that in part is why?
03:12Intracranial Athero has such
03:14a high rate of recurrence.
03:17The other thing that is of course
03:21important is that intracranial arteries
03:24are not the same as extracranial,
03:27so you can see here in broad terms that.
03:31The structure in cross section of an
03:35intracranial artery is very different
03:37than that of an extracranial,
03:40such as the carotid artery and for one thing,
03:45intracranial arteries are thinner.
03:47They sit in spinal fluid, they don't have.
03:52By and large vasa vasorum it.
03:56It effectively is a different blood vessel,
04:00so that too I think.
04:02Is why many of the treatments that work
04:05in carotid disease don't work intracranial,
04:08so the broad hypothesis of captive
04:12MRI is that with MRI biomarkers
04:16and I'll go into them briefly,
04:19but with this additional
04:21information we get on MRI,
04:24we will be able to better risk
04:27stratify patients with DIECASTS and.
04:31That that is very similar
04:34to what perfuse diecasts UM
04:36is looking at, and I think
04:39both Shadi and I recognize that
04:42stenosis is an important metric.
04:45We're not saying that we
04:47want to supplant stenosis,
04:48but that we can add information to stenosis.
04:53And that may well help us identify
04:56patients who fail medical management.
05:00So in Captiva we may find that
05:03low dose rivaroxaban and aspirin
05:05lowers the rate of recurrent stroke,
05:08perhaps to 10%.
05:10But why did those 10% still
05:14fail medical management and?
05:18The multimodal MRI markers
05:20that were interested in UM,
05:24we anticipate patients will spend about
05:2750 minutes in the scanner in addition to.
05:32Sort of conventional diffusion imaging
05:36volumetric imaging will get standard
05:39perfusion imaging the main exposures,
05:42though,
05:43will be quantitative MRA which you
05:47might be familiar with from the
05:50Vera TOS study wall shear stress,
05:53which is an emerging technique
05:56that looks at the disruption
06:00of flow around plaque.
06:02And then inflammation of plaque
06:05on vessel wall or black blood Mr.
06:09Uhm,
06:10I won't show up numerous a data
06:15fields in this presentation,
06:18but these all have been shown
06:21in prospective studies to be
06:24associated with recurrent stroke.
06:27All smaller studies and and a
06:32suboptimal in in various ways,
06:35which I won't go into.
06:37But certainly they have.
06:40Preliminary data suggesting that they
06:42could be predictive of recurrent stroke.
06:46And I think when looking at the rationale
06:49for an ancillary MRI study to Captiva,
06:53UM,
06:54it is an opportunity that if we miss it,
06:59it really would be a major loss.
07:03I think for the field,
07:04because regardless of if Captiva
07:08ends up being a positive trial,
07:10and I think there's ample reason
07:14to believe it will be.
07:16There will be trials subsequent to Captiva,
07:20and if we can identify the patient
07:23population who's going to fail the new
07:27standard of care of medical management,
07:30that is an important piece
07:33for trials moving forward.
07:37And Captiva does not have standardized
07:40imaging and and as somebody who does
07:43a lot of secondary data analysis,
07:46I think it's it's a responsibility
07:50of mine to try to give back to
07:54the community by hopefully giving
07:59some standardized imaging and
08:02other imaging in addition to the
08:05three exposures that I mentioned.
08:07To accompany the outcome
08:09adjudication Captiva,
08:10which will be excellent and the
08:15final reason is that I think there
08:20are other hypotheses related to that
08:24additional Mr Data such as you know,
08:28do we see signal for cognitive outcomes?
08:33There are some cognitive
08:35outcomes collected in Captiva.
08:37But getting a standardized MRI will
08:40allow us to circle back and say why.
08:43Why do we see decline in cognitive function?
08:48Is it because there's cortical atrophy?
08:51Is it because the white matter
08:53hyper intensity volume increased?
08:57And I think I'll skip this because, uhm?
09:00It, uh, our inclusion
09:03exclusion mimics Captiva.
09:05We would want to obtain the MRI
09:08within 14 days of captive enrollment.
09:12And our primary outcome would be
09:14recurrent stroke in the vascular
09:17territory of the index stroke.
09:20We will have a 12 month follow up
09:23MRI so the study includes a baseline
09:27and follow up Mr UM and that would
09:31allow us as a secondary outcome to
09:35have asymptomatic silent infarcts in
09:39addition to the symptomatic infarcts.
09:42As I mentioned,
09:43will also is a tertiary outcome.
09:46Look at cortical thickness and
09:49white matter hyperintensities.
09:51Uh, it's a pretty simple ancillary.
09:54We're only collecting data from the imaging,
09:58so there's an MRI within 14 days and then
10:01one at completion of Captiva, 12 months.
10:06Uhm, we think will need about 300
10:10patients to reliably show and outcome.
10:15Uhm. We mainly powered it on Q.
10:18Murray.
10:18Although actually many of the assumptions
10:21hold for the other exposures as well.
10:26And when getting those 300 patients,
10:30multimodal MRI is not something
10:33that every site can do,
10:35and stroke net.
10:37Certainly elements of the MRI
10:40are going to be challenging,
10:43although we think within the
10:46the realm of feasibility.
10:48But we are proposing picking 30 high
10:54enrolling sites and we think those.
10:5730 sites will actually account for
10:59about 50% of captive a sample,
11:02so if you look at the enrollment
11:05in Arcadian most up to date,
11:08well it's a couple weeks ago.
11:11But what you'll see is that if you
11:14take all of the sites and then sort
11:18of focus on the top third there,
11:22you get at least half of the
11:25enrollments in the overall trial.
11:28Uhm?
11:28The sample size of Captiva
11:31is about 1600 patients,
11:34so we think we'd have over 800
11:36eligible patients at the 30 sites.
11:41Arcadia CSI is enrolling quite well.
11:46We think we didn't roll
11:48even better than that,
11:49and we don't have any additional
11:53data collection apart from the MRI.
11:56Uhm, and, uh, I think I'll close
11:59there 'cause we're out of time,
12:02but thank you so much honey for
12:05letting me briefly present that. Thank
12:08you so much Adam. This was certific.
12:12We definitely need better treatments
12:14for patients with symptomatic icad.
12:17As you mentioned, the risk of recurrence
12:19is high and you know there are
12:22multiple reasons why patients recur,
12:24so it's a comprehensive.
12:26Understanding of these reasons is very
12:30important than secondary prevention.
12:33I don't see any.
12:35I I see question from Kevin.
12:39And I'm just gonna read the the question,
12:41uh, so for each of your approaches is
12:45the idea to one identify patients at
12:49higher risk or patients that may be
12:52more likely to benefit from mechanical
12:54intervention versus medical treatment.
12:58I think Kevin's question is for me, although
13:02it could apply to profuse eyeglasses.
13:08I think the idea is to identify
13:10patients at higher risk.
13:11Come with the idea of both
13:16understanding plaque biology.
13:18I didn't talk about it in my slides,
13:20but one of the things we really
13:22want to do is look at the evolution
13:25of of these plaques with sort of
13:28multimodal high resolution Mr.
13:30Over a year. But uhm,
13:33that's that's secondary to being
13:37able to identify inclusion.
13:39Exclusion for future studies.
13:44Great, thank you so much
13:46for this and thank you so
13:48much everyone for attending.
13:50We had great sessions today.
13:53I personally have learned so much from
13:56each presentation and I'm sure most
13:58of us if not all feel the same way.
14:01Now I'll turn it over the Kevin.