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INFORMATION FOR

Research Talk - Adam de Havenon - Yale - YNHH

October 27, 2021
  • 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.