CVM Grand Rounds December 3, 2025

Name: CVM Grand Rounds December 3, 2025
Uploaded: 2025-12-03T19:02:30.7733333Z
Duration: 1 h 9 min 42 s

December 03, 2025

Information

ID: 13672
To Cite: DCA Citation Guide

Download Transcript

02:53Yeah.
05:19Alright. Good afternoon, everyone.
05:25It's my pleasure to welcome
05:26you all here to to
05:27Grand Rounds,
05:28on behalf of,
05:30doctor Clark who's at at
05:31SRC and doctor Chung and
05:32doctor Mora.
05:35As you can see on
05:35the screen,
05:36there is the CME
05:38code that you can text
05:40for CME.
05:46Here are the upcoming,
05:48faculty meet or, grand rounds
05:50lectures.
05:52Reminder that, next week will
05:54be the faculty research meeting
05:55and then the required
05:57annual building training for,
05:59for attendings,
06:00Zoom only,
06:02before we, take a holiday
06:04break.
06:05A disclosure and accreditation slide.
06:08And now it's really my
06:09pleasure to begin the introduction
06:11since there's two fellows presenting.
06:14There needs two people to
06:15be to introduce
06:16them to you today. So
06:17I'm gonna provide a a
06:18brief introduction and then turn
06:20it over to doctor Maina
06:21for a more formal introduction.
06:23You know, as a parent,
06:24there's a saying that you
06:26love all your children equally,
06:28but you like some more
06:29than others. And so,
06:32just like with fellows,
06:34you love all of them
06:35equally even you like some
06:36more than others. And it's
06:37my it's my, real privilege
06:39to,
06:41introduce you to, to,
06:43Lindsay and Jake today to
06:45give their,
06:46sort of ultimate grand rounds
06:48discussing their work that's culminated
06:50over their training with us.
06:52And what I'd like to
06:54just impart is,
06:56how we've all watched them
06:59grow and develop as
07:01investigators and as clinicians,
07:03but they've all both taken
07:04advantage of tremendous opportunities, made
07:06them their own, and been
07:07successful across multiple dimensions of
07:09their career. We're so excited
07:11to hear from you all
07:12today about your your work
07:14and the future of peripheral
07:15vascular interventions. And with that,
07:17I'll turn it over to
07:18Carlos for a more formal
07:19introduction. Thank you.
07:24Thanks, Ed.
07:26So
07:27thank you everybody, for coming
07:28and joining us for those
07:29that are remote.
07:30So I have the privilege
07:32to present,
07:33two
07:35wonderful
07:36fellows, but more important, two
07:38wonderful
07:39human beings that I had
07:40the pleasure and privilege
07:42to meet since they were
07:45real,
07:46little kids all almost.
07:48And I'm gonna elaborate. I'm
07:50gonna start with Lindsay. Lindsay,
07:53obviously, is a fellow here.
07:54She was a member of
07:55the inaugural class at the
07:57Frank Nader,
07:58School of Medicine at Quinnipiac
08:00University,
08:01where she earned a master
08:03in public health degree,
08:05from New York Medical College.
08:06She also did her residency
08:08here at Yale where she
08:10was a chief resident,
08:11then became a cardiology fellow,
08:14clinical cardiology fellow. Then she
08:16did a t thirty two
08:17training,
08:18with our,
08:20Vamos group.
08:21And,
08:23she is eager,
08:26poised to continue,
08:28within the Yale cardiovascular medicine
08:29as a faculty, which she
08:31will join. Thanks to the
08:32effort of Eric and the
08:33section of the department to
08:35retain her.
08:36On a personal note, however,
08:38I met Lindsay, I don't
08:39know, when she was a
08:40resident, I think, an intern
08:41maybe.
08:42And in a random occasion,
08:44she approached me as I
08:45was charting,
08:46on the floor and said,
08:47you know, I would like
08:48to do some cardiology research,
08:50and that's how we started
08:51talking.
08:52Since then,
08:54I became, her mentor. And,
08:56to be honest with you,
08:57one of the greatest pleasures
08:58of being a faculty member
08:59is that mentor mentee relationship
09:01that you can develop. And
09:03for me, these are the
09:04two examples of what that
09:05relationship means and looks like.
09:08Lindsay has done above and
09:10beyond my wildest expectations. She's
09:12an incredibly
09:13talented physician, incredible at the
09:15bedside manner. She told me
09:17how to use effectively,
09:20spreadsheets and Excel. She's incredibly
09:22good about it.
09:24And she developed an interest
09:25and passion on vascular medicine,
09:27which she shares with me
09:29and the rest of my
09:30team.
09:31And I look forward,
09:32to what she's gonna do
09:34as a faculty member, which,
09:36is going to be phenomenal.
09:39Now going on to Jake.
09:42Jake obviously did a fellowship
09:44in general cardiology here and
09:46in the vascular interventions and
09:48interventional cardiology.
09:50Jake and I share a
09:51lot of different things.
09:54Certainly, one of them is
09:55we have a similar father
09:57figure, slightly different. So her
10:00father
10:00his father, I'm sorry, doctor
10:02Michael Clemen, taught us a
10:04lot of different things that
10:05we practice and do every
10:06day,
10:07as we perform procedures.
10:09Jay came and spent two
10:11years of doing clinical,
10:13outcomes research with our group
10:15where he where he excel
10:17and developed paradigms that have
10:19been applied in different case
10:20scenarios that we perform in
10:22the vascular interventions.
10:24We are also lucky and
10:25fortunate to keep him as
10:26a faculty member when he
10:28finishes his endovascular fellowship, and
10:30he'll join the vascular medicine
10:31group, and we're equally excited
10:33about that. Both of them
10:35are gonna talk to us
10:36about carotid intervention.
10:38Another one of my kids.
10:41Carotid stenting
10:43has undergone
10:47multiple challenges over the years.
10:50In fact, I suggested a
10:51title to the grand rounds,
10:53which was
10:54how many times can you
10:56be taken down before you're
10:57left alone?
10:59But they felt that it
11:00was a little bit too
11:01much. So I I said,
11:02fine. We can go with
11:04something else. So without further
11:06ado, I'll let them present,
11:08the data about carotid,
11:10revascularization.
11:11Lindsey?
11:20Alright. Thank you very much,
11:22doctor Mena and doctor Miller,
11:23for the introductions. We are
11:24very excited to be here
11:25today to do our peripheral
11:26vascular case conference. So Jake
11:29and I are going to
11:29be talking about the contemporary
11:31management of carotid artery stenosis.
11:36Here are our disclosures.
11:39And for our talk today,
11:41we're going to start by
11:42reviewing the background and historical
11:44context of carotid artery stenosis.
11:46As doctor Menna mentioned, there's
11:48a very robust history there,
11:49so we'll break down, not
11:51only the practice patterns, but
11:52some of the evidence behind
11:53the interventions that we do.
11:55We'll do this through a
11:57case based discussion, which is
11:58gonna highlight contemporary management issues
12:01and things that we come
12:02up with every day in
12:03clinic.
12:04We'll summarize the current state
12:05of the literature and talk
12:06about the evolving guideline landscape,
12:09and then we'll conclude by
12:10discussing the CREST two trial,
12:11which was recently published in
12:13the New England Journal of
12:14Medicine and its implications for
12:16clinical practice.
12:19So we will start today
12:21with the case.
12:24So this is a sixty
12:25year old man who was
12:27referred to our clinic for
12:28carotid artery evaluation.
12:30So he has a history
12:31of Hodgkin's lymphoma with prior
12:33neck radiation, and he underwent
12:35a routine thyroid ultrasound as
12:37part of his malignancy surveillance.
12:39During that ultrasound, he was
12:41found to have carotid artery
12:42calcifications
12:43incidentally.
12:45This prompted a formal carotid
12:46ultrasound, which was mildly abnormal
12:48and he was followed annually.
12:50He had a repeat ultrasound
12:52earlier the month before we
12:53saw him that showed worsening
12:55of his stenosis and for
12:56which he was referred to
12:57our clinic.
12:59Prior to this, he has
13:00no history of stroke or
13:01TIA,
13:02no significant neurological
13:04symptoms, and he was otherwise
13:06asymptomatic from a vascular perspective.
13:09His other past medical history
13:10is shown here. He has
13:11hypertension,
13:12hyperlipidemia,
13:14diabetes,
13:15chronic kidney disease, and a
13:16remote history of CAD with
13:18a PCI.
13:19His medications are also shown.
13:21He's on pretty standard therapy,
13:23including aspirin, rosuvastatin,
13:25lisinopril,
13:27carvedilol,
13:27and and an SGLT two
13:29inhibitor.
13:32On exam in our office,
13:33he had a blood pressure
13:34of one thirty over sixty
13:35eight and a heart rate
13:36of seventy beats per minute.
13:38Labs were notable for a
13:39creatinine of one point five,
13:41which is his baseline, an
13:42LDL of twenty six on
13:44statin therapy, and a hemoglobin
13:46a one c of seven
13:47point six percent.
13:49On exam, he had no
13:50appreciable carotid bruit, and his
13:52neurological
13:53exam was nonfocal.
13:55He had an NIH stroke
13:56scale and modified ranking score
13:58of zero.
14:02Oops.
14:03So this is his most
14:04recent carotid ultrasound prior to
14:06presenting to our office.
14:08It was noted that he
14:09had mild stenosis of the
14:10right carotid artery with a
14:12peak systolic velocity of eighty
14:13seven. On the left, however,
14:15you can see in the
14:16ultrasound image,
14:17there's a mixed plaque in
14:18the internal carotid artery with
14:20Doppler flow acceleration
14:22through the lesion.
14:23The peak systolic velocity of
14:25that lesion was two hundred
14:26and forty six centimeters per
14:28second, which correlates with a
14:30seventy percent stenosis.
14:31This velocity was overall increased
14:34from his prior ultrasound two
14:35years ago, and it was
14:36concerning for severe left carotid
14:39artery stenosis.
14:42So here we have a
14:43well appearing sixty year old
14:45man with some risk factors
14:47and a progression of carotid
14:49disease now with a seventy
14:51percent stenosis on on the
14:52left. He's asymptomatic
14:54and otherwise feeling well. So
14:56now we need to ask
14:57ourselves, what is the appropriate
14:59management of this patient?
15:02So to answer this question,
15:04we're gonna go through the
15:05basics of carotid artery stenosis
15:07and review some evidence based
15:08management.
15:12So carotid artery stenosis is
15:14a narrowing of the carotid
15:15artery lumen traditionally from atherosclerotic
15:18plaque development.
15:20There are other entities like
15:21vasculitis and fibromuscular
15:23dysplasia that can impact the
15:25carotid arteries, but, traditionally, we're
15:27thinking about plaque and atherosclerotic
15:29disease.
15:30The most significant risk associated
15:32with chronic stenosis is the
15:34risk of stroke.
15:36It's associated with ten to
15:37twenty percent of all ischemic
15:39strokes.
15:41And strokes in these patients
15:42can be due to thromboembolism
15:44from plaque rupture
15:46or from hemodynamic
15:47compromise from a significant lesion.
15:49Now it goes without saying
15:51that stroke's a significant cause
15:53of morbidity and mortality, especially
15:55as patients age.
15:57Our risk factors for carotid
15:58stenosis
15:59mirror the traditional risk factors
16:01that we see for other
16:02types of atherosclerosis,
16:03and they include,
16:05advanced age, hypertension,
16:07smoking, dyslipidemia,
16:09diabetes,
16:10and prior neck radiation like
16:12our patient.
16:13And in regards to prevalence,
16:15it's estimated that about one
16:16percent of all adults over
16:18the age of sixty five
16:20have at least a seventy
16:21percent stenosis.
16:23And in terms of outcomes,
16:24patients with carotid stenosis
16:27potentially have a risk for
16:28poor cognitive outcomes.
16:30It's not yet known what
16:32role carotid stenosis might play
16:33in cognitive function and cognitive
16:35decline,
16:36but emerging evidence suggests that
16:38there may be a negative
16:39association.
16:43The diagnosis of carotid artery
16:44stenosis typically starts with duplex
16:46ultrasound.
16:47There's standardized criteria that we
16:49can use to estimate the
16:51percent stenosis based on the
16:52degree of elevation and the
16:54velocities.
16:55Ultrasound also provides an anatomic
16:57assessment where we can see
16:58plaque characteristics and luminal narrowing.
17:02There's more advanced imaging options
17:03as well, including CTA and
17:05MRA,
17:06but, typically, these are used
17:07more to confirm anatomy,
17:10and to evaluate plaque morphology
17:12and guide procedural planning.
17:14The key is correlating the
17:16imaging with the clinical presentation,
17:18especially to determine whether someone's
17:20symptoms are attributable to the
17:22territory in question.
17:27Once diagnosed,
17:28distinguishing symptomatic from asymptomatic
17:31carotid stenosis is essential.
17:33A patient is considered symptomatic
17:35if they've had a focal
17:36neurological
17:37event
17:38within the last six months
17:40on the ipsilateral side of
17:42where the carotid disease is.
17:44And in terms of neurological
17:45deficits, this includes ischemic stroke,
17:48TIA, or retinal ischemia,
17:50but does not include
17:52nonspecific symptoms like dizziness,
17:54syncope,
17:55headache, or cognitive changes.
17:58This definition drives almost all
17:59of the guideline and trial
18:01based recommendations, so it's important
18:02to classify our patients as
18:04they're presenting with disease.
18:08There are three mainstays of
18:10treatment for carotid artery stenosis.
18:12The first and cornerstone of
18:13therapy is optimal medical management,
18:16which includes the use of
18:17statin therapy for a target
18:18LDL less than seventy,
18:20an antiplatelet
18:21agent, and controlling disease modifiers
18:24like hypertension and diabetes.
18:26Lifestyle modifications are also recommended
18:28like smoking cessation.
18:30For interventions, there is carotid
18:32endarterectomy,
18:33which is a surgical approach,
18:35and carotid stenting, which can
18:37be endovascular
18:38or surgical.
18:39The appropriate choice or combination
18:42of treatments for each patient
18:43is a nuanced decision, and
18:45we'll go into more detail
18:46on that in the coming
18:47slides.
18:50So for our patient, this
18:51raises several questions.
18:53What role does optimal medical
18:54therapy play in preventing or
18:56delaying the development of symptoms?
18:59And given that he's asymptomatic,
19:00would he benefit from an
19:02intervention at this time?
19:03And if so, how do
19:05we choose between endarterectomy
19:06and carotid stent?
19:08And most importantly,
19:09how do these interventions affect
19:11his future stroke risk?
19:15So to understand the risks
19:16and benefit of each treatment
19:17modality and for our patient,
19:19we're gonna revisit some of
19:20the foundational trials that help
19:22shape the carotid stenosis landscape.
19:26So historically,
19:28carotid disease management has gone
19:29through several eras.
19:31In the nineteen fifties, DeBakey
19:33and Eastcott introduced carotid endarterectomy,
19:36and for decades, it was
19:37the only intervention to treat
19:39these patients.
19:41In the nineties, trials like
19:42NASIT established a clear benefit
19:44in endarterectomy
19:46in select symptomatic and asymptomatic
19:48patients.
19:50In the two thousands, carotid
19:51artery stenting emerged,
19:53prompting debate around equivalence and
19:55indications.
19:57And today, we're entering a
19:58new paradigm
19:59where medical therapy is extraordinarily
20:01effective, and the benefit of
20:03revascularization
20:04needs to be determined above
20:06and beyond the benefit of
20:07medical therapy alone.
20:12The initial wave of carotid
20:13stenosis trials began with the
20:15NASET trial. It was published
20:17in nineteen ninety one, and
20:18it was the first large
20:20scale randomized trial that enrolled
20:22over two thousand patients with
20:24symptomatic carotid stenosis of greater
20:26than seventy percent.
20:28In that study, patients were
20:29randomized to endarterectomy
20:31plus medical therapy
20:33versus medical therapy alone.
20:35The study found that endarterectomy
20:37dramatically reduced ipsilateral stroke in
20:40patients
20:40that had greater than seventy
20:42percent stenosis
20:43with an absolute risk reduction
20:44of seventeen percent.
20:46These findings were further confirmed
20:48in the ECST trial with
20:49a similar population.
20:52A few years later, there
20:53were trials that emerged looking
20:54at asymptomatic
20:56disease. So ACAS and ACST
20:58explored the role in asymptomatic
21:00patients with greater than sixty
21:02percent stenosis,
21:03but they only showed a
21:04modest benefit to endarterectomy.
21:06Around one percent absolute risk
21:08production for stroke per year
21:10versus medical therapy alone.
21:14And while these early trials
21:16establish endarterectomy as the standard
21:18of care, especially for patients
21:20with symptomatic and severe disease,
21:22it's essential to remember that
21:23these trials were conducted in
21:24a very different time. The
21:26medical therapy that we use
21:28today was not widely available
21:30or routinely used.
21:31In these trials, aspirin was
21:33the only antiplatelet
21:34agent. There were no p
21:35two y twelve inhibitors.
21:37There was limited statin use,
21:38and the average LDL for
21:40patients in these studies ranged
21:41from one thirty to one
21:43fifty.
21:44There were also no strict
21:45blood pressure targets. Patients were
21:47often hypertensive with systolic blood
21:49pressures in the one forties
21:50to one sixties,
21:51and lifestyle counseling was not
21:53routine. There was a significantly
21:55higher rate of smoking in
21:56this population in the eighties
21:57and nineties than there is
21:58today.
21:59With this in mind, it's
22:00difficult to know exactly how
22:02much benefit the surgical intervention
22:04had itself in the absence
22:06of optimal medical therapy.
22:10So as stenting emerged in
22:11the two thousands, there were
22:13multiple trials that compared carotid
22:15artery stenting directly to carotid
22:17endarterectomy.
22:18This includes the CABITAS trial,
22:20EVA three s, and SPACE,
22:22which came out in the
22:23early two thousands.
22:25These initial studies, however, were
22:26very small. They only enrolled
22:28around three hundred to five
22:30hundred patients,
22:31and the results were mixed
22:32to poor.
22:34The periprocedural
22:35stroke or death rates in
22:36the carotid stenting arms were
22:38as high as ten percent.
22:40But it's important to note
22:41that these were the first
22:42carotid stent trials. These were
22:44earlier devices. They had high
22:46embolic protection or potential,
22:48limited operator experience, and routine
22:51embolic protection during the procedure
22:53was not used.
22:54However, as the technology,
22:56the technique, and experience improved,
22:59SAFIRE was the first study
23:00that showed noninferiority
23:02of carotid stenting
23:04to carotid endarterectomy
23:06in high risk surgical patients,
23:08which led to its initial
23:09FDA approval.
23:11There was a pooled analysis
23:12of the early carotid stent
23:14studies done by Brott et
23:15al. In two thousand and
23:16nine. And it showed that
23:18while carotid artery stenting had
23:20a higher thirty day periprocedural
23:22stroke risk, once that risk
23:24was excluded,
23:25long term outcomes between carotid
23:27stent and endarterectomy
23:28were similar.
23:32So this led to the
23:33CREST one trial.
23:34CREST one was the first
23:36large scale randomized trial that
23:38compared carotid stenting directly to
23:40endarterectomy.
23:41It enrolled twenty five hundred
23:43patients who are both symptomatic
23:45and asymptomatic
23:46across over a hundred and
23:48thirty centers in the US
23:49and Canada.
23:50Patients were randomized one to
23:52one to carotid stenting with
23:53embolic protection
23:54versus traditional endarterectomy.
23:57And all patients were optimized
23:59on best medical therapy.
24:01The primary endpoint in this
24:02trial was a composite of
24:04stroke, MI, or death within
24:06thirty days combined with ipsilateral
24:08stroke up to four years.
24:13The study found that there
24:14was no significant difference in
24:16the composite endpoint
24:17between patients who underwent carotid
24:19stenting versus endarterectomy,
24:22demonstrating that carotid stenting was
24:24non inferior to endarterectomy
24:26overall.
24:27But it's important to note
24:28that that the periprocedural
24:29risk profiles in these two
24:31cohorts differed.
24:33Carotid stenting still tended to
24:35have more periprocedural
24:36strokes,
24:37but carotid endarterectomy
24:39had more periprocedural
24:40MIs.
24:41And age also mattered. Patients
24:43over the age of seventy
24:45had a higher stroke risk,
24:46and they tended to do
24:47better,
24:49with carotids,
24:50endarterectomy
24:51as opposed to stenting due
24:52to arch anatomy.
24:55So one of the reasons
24:56that the paraprocedural
24:57event rate was so low
24:58in this study was that
25:00there was significant effort made
25:02to have high quality operators
25:04enroll.
25:05The event rates were lower
25:06in earlier trials due to
25:08medical therapy and operator experience.
25:11In order to be an
25:11enrolling operator in this study,
25:13clinicians needed to submit case
25:15logs,
25:16demonstrate low procedural event rates,
25:18and perform observed cases in
25:20order to be accepted and
25:22selected to be an enrolling
25:23provider.
25:24So this is one of
25:25the reasons why CREST one
25:27confirmed that both procedures are
25:28effective and safe when performed
25:30by experienced operators.
25:35It's also important to note
25:36that in the ten years
25:37between our first study, NASET,
25:39and CREST one, the overall
25:41stroke rate in this population
25:42decreased significantly
25:44from an annual stroke rate
25:45of five to six percent
25:47down to one to two
25:48percent in this population.
25:50The advances in medical therapy
25:52and guidelines
25:53recommended
25:54management of comorbidities, and it
25:55was a significant impact for
25:57our patients.
25:58DAPT became more available, high
26:00intensity statins and other lipid
26:02agents were being used, and
26:04blood pressure guidelines were more
26:05strict.
26:06There are also more pharmacologic
26:08agents available to manage diabetes.
26:10So this leads us to
26:11question, and I hesitate to
26:13do this in a room
26:14full of my interventional colleagues.
26:16Do we need procedures?
26:19Just how much additional benefit
26:20are our patients getting from
26:21the interventions above and beyond
26:23the benefit of the optimal
26:25medical therapy that we have
26:26for them today?
26:29So this concept of intervention
26:31versus medical therapy is the
26:33newest paradigm that's being studied
26:34for patients with carotid stenosis.
26:37There were two recently published
26:38trials on this topic, space
26:40two and ECSC two.
26:42But both trials enrolled slightly
26:44different patients, but they compared
26:46any type of intervention. So
26:48endarterectomy
26:49or stenting plus medical therapy
26:51versus medical therapy alone.
26:53But these trials were fraught
26:55with challenges.
26:56Space two was only able
26:57to enroll five hundred of
26:58their planned thirty six hundred
27:00patients, and ECST
27:02only enrolled four hundred.
27:04And while both studies found
27:05no difference in stroke MI
27:07or death between the two
27:09arms, the studies were significantly
27:11underpowered, leading us to continue
27:13to question the validity of
27:14their results.
27:17So the data that we've
27:18reviewed so far is largely
27:19reflected in the guidelines in
27:20the management of carotid artery
27:22stenosis.
27:23This is a snapshot of
27:24the twenty twenty one
27:25and American Stroke Association guidelines
27:28for the prevention of stroke
27:29after stroke or TIA. And
27:31this reaffirms that for symptomatic
27:33patients with a greater than
27:34or equal to seventy percent
27:36stenosis
27:37and low periprocedural
27:38risk,
27:39revascularization,
27:40typically endarterectomy,
27:42is a class one recommendation
27:44and should be performed by
27:45experienced operators.
27:47Optimal medical therapy, as we
27:49have discussed as well, is
27:50also a class one recommendation.
27:53And for patients with moderate
27:54symptomatic stenosis in the fifty
27:56to sixty nine percent range,
27:58and arterectomy is reasonable in
27:59carefully selected patients,
28:01factoring in age, sex, symptom
28:03type, and surgical risk.
28:07The data for carotid stenting
28:08in symptomatic patients is not
28:10quite as strong, but still
28:11good. There's a two a
28:12and two b recommendation for
28:14stenting in patients with greater
28:15than seventy percent stenosis,
28:17especially if they're at an
28:18increased risk or if there
28:19are anatomical concerns,
28:21but optimal medical management remains
28:23foundational.
28:24These guidelines also emphasize shared
28:26decision making and individual risk
28:28assessment.
28:31The guideline recommendations for asymptomatic
28:34patients are less robust.
28:36All guidelines agree that there's
28:38no role for asymptomatic
28:40screening of patients,
28:41but they do support targeting
28:43screening of patients who are
28:44high risk. So patients who
28:46have already other established atherosclerotic
28:49disease or symptoms should definitely
28:50undergo screening for aortic stenosis.
28:53And all the guidelines also
28:55agree that optimal medical therapy
28:56for everyone with carotid stenosis,
28:58symptomatic or not, is indicated.
29:01But regarding vascular revascularization,
29:03the twenty twenty one Society
29:05of Vascular Surgeons guideline notes
29:07strong evidence for the recommendation
29:09of endarterectomy
29:11and moderate evidence for carotid
29:12stenting.
29:14However, in asymptomatic patients with
29:16low surgical risk, it's still
29:18unclear what we should do.
29:19The and ASA guidelines focused
29:22only on symptomatic disease. And
29:24for asymptomatic patients, they stated
29:26that revascularization
29:27can be considered, but the
29:28level of evidence was not
29:29very strong.
29:33So this leaves us with
29:34our current management pathway,
29:36optimal medical therapy for all,
29:38and intervention for symptomatic patients
29:40with moderate or severe stenosis.
29:42But for our asymptomatic patients,
29:44our data is limited and
29:45the guidelines aren't very clear.
29:49So for individuals with carotid
29:51artery stenosis like our patient
29:52in this case, who are
29:53asymptomatic
29:54with a greater than seventy
29:55percent stenosis,
29:57the benefit of intervention above
29:58and beyond optimal medical therapy
30:00is not clear. Further, the
30:02choice of intervention, be it
30:04endarterectomy
30:04or carotid stent, has had
30:06mixed results.
30:07So we need more data
30:08to help guide this choice
30:10and allow us to make
30:11the best clinical decision possible
30:12for our patient.
30:14And with that, I'll turn
30:15it over to doctor Clemen.
30:24Thank you, Lindsay, and,
30:25thank you, doctor Miller and
30:27doctor Mena, for the introduction.
30:30So I'm gonna be talking
30:31about the CREST two trial,
30:32which was just, simultaneously
30:35presented at Veith and published
30:36in the New England Journal
30:37of Medicine last month.
30:39Our teams here at Yale,
30:41neurology, vascular surgery,
30:43cardiology,
30:44and, research teams worked in
30:46concert to make Yale one
30:47of the top recruiting sites
30:48for this particular trial.
30:53As Lindsay has extensively reviewed,
30:55there's still some outstanding questions
30:57regarding the management asymptomatic crowded
30:59stenosis.
31:00Systematic reviews of these older
31:02studies have shown a reduction
31:03in mortality and near twofold,
31:05risk reduction in ipsilateral stroke
31:07for revascularization of asymptomatic
31:09disease.
31:11But as we heard from
31:12Lindsay, some of the newer
31:13or more recent randomized controlled
31:15data,
31:17has been, flawed,
31:19specifically, UCSD two and space
31:21two, which were significantly underpowered.
31:25These, however, did not show
31:27a difference,
31:28between revascularization and medical therapy.
31:31But given the limitations in
31:32these studies and the outstanding
31:33questions,
31:34CREST two was designed and
31:36ongoing, to help answer,
31:39what were the questions that
31:40remained.
31:44So CREST two is actually
31:45designed as two parallel,
31:47studies. So an endarterectomy
31:49plus intensive medical management arm,
31:51versus intentsable medical management alone.
31:54And then as a separate
31:54study, a carotid stenting and
31:56intensive medical management versus intensive
31:58intensive medical management alone.
32:01To be clear, there's no
32:02direct comparison between stenting and
32:04endarterectomy in this particular trial.
32:07This was a multicenter randomized
32:09observer blinded study that was
32:12conducted a hundred and fifty
32:13five sites worldwide, including here
32:14at Yale.
32:16I've listed the, inclusion and
32:18exclusion criteria below. But briefly
32:21for inclusion criteria,
32:22patients had to be thirty
32:23five years or older and
32:25essentially had to,
32:27have had no symptoms in
32:28the last a hundred and
32:29eighty days. So they could
32:30have had a prior TIA,
32:31for example, before that hundred
32:32and eighty day mark.
32:34And they had to have
32:35proven,
32:36severe disease,
32:38so either by duplex,
32:40with the listed requirements,
32:43below here. So a peak
32:44systolic that's two hundred and
32:46thirty centimeters,
32:47per second or greater,
32:48and then diastolic velocity that
32:50was a hundred centimeters per
32:51second or greater,
32:53and then, a ratio between
32:54the internal and common carotid,
32:57that was greater than four,
32:58and then confirmatory evidence from
33:00a CTA or MRI.
33:03Or, they could have had
33:04an angiogram alone, which documented,
33:07seventy percent or more stenosis.
33:09For exclusion criteria,
33:11anyone who had a previous
33:12disabling stroke was, excluded.
33:15These,
33:16were judged based on a
33:17modified ranking score of two
33:19or higher.
33:20Unstable angina, atrial fibrillation prompting
33:23anticoagulation,
33:24other high risk sources of
33:25emboli,
33:28CKD, so the creatinine greater
33:29than two point five or
33:30a GFR that's less than
33:31fifty,
33:32and more advanced heart failure
33:33with EFs that were less
33:34than thirty percent, and
33:36any lateral occlusion of the,
33:38internal or common carotid.
33:41There are also endarterectomy
33:42and stenting specific exclusion criteria,
33:44which I did not list
33:45here.
33:46For endarterectomy,
33:47that included,
33:48severe at least two vessel
33:50proximal coronary disease,
33:52unsuitable anatomy. So, like, with
33:54our patients, someone who had
33:55prior, neck radiation or had
33:57a radical neck dissection, for
33:58example,
33:59or allergies to heparin or
34:01bivalirudin.
34:02For carotid stenting,
34:04the specific exclusion criteria included
34:06a documented history of contrast
34:08allergy,
34:09a type three aortic arch,
34:10critical or occlusive ileofemoral disease,
34:14or severe angulation or calcification
34:15in the common or internal
34:17carotid, that would make the
34:18procedure,
34:19difficult and,
34:21higher risk.
34:24One of the unique aspects
34:25about both of the CREST
34:27trials and specifically here, about
34:28CREST two, was that,
34:31the vetting of high quality
34:33operators.
34:34So, for each site that
34:36was involved,
34:37all of the proceduralists,
34:39that were included, that were
34:40allowed to enroll patients had
34:41to, be approved by a
34:43committee.
34:44In order to do so,
34:45they had to submit, patient
34:47logs. So for, interventionalist,
34:49those that were performing carotid
34:50stenting,
34:52they had to submit,
34:54all case logs from the
34:55preceding twelve months and then,
34:57submitted procedural reports and angiograms
34:59for an additional twenty five
35:01patients,
35:02depending on their overall case
35:03volume.
35:04The surgeons submitted their prior
35:06fifty consecutive endarterectomies
35:09and required documentation of periprocedural
35:11stroke and death rates that
35:12were less than three percent.
35:14Overall, approximately fifty percent of
35:16interventionalists
35:17that applied,
35:19were included or were allowed
35:21to enroll patients in the
35:22study in the carotid stenting
35:23arm.
35:24And over ninety percent of
35:25the surgeons that applied were
35:26approved,
35:27to enroll
35:29endarterectomy arm.
35:31And this is in contrast
35:32to many of the other,
35:33carotid revascularization studies that Lindsay
35:35has already presented on.
35:39Regardless of which study,
35:42or which arm patients were
35:43randomized to each patient was
35:44subject to the same intensive
35:45medical therapy
35:47regimen and target goals,
35:48with the exception of antiplatelet
35:50regimens,
35:52patients who were randomized to
35:53endarterectomy
35:54received periprocedural
35:56aspirin, a full dose three
35:57hundred and twenty four milligrams,
35:58and those,
35:59randomized to, stenting received aspirin
36:02and Plavix.
36:04Regardless of, randomization,
36:06best medical therapy was, managed
36:08by site investigators,
36:10from neurology
36:14primary targets were systolic blood
36:16pressures less than one forty,
36:18or less than one thirty
36:19if patients were diabetic and
36:20LDL cholesterol goals that were
36:22less than seventy. And these
36:23were based on the available
36:24guidelines,
36:25at that time. And remember,
36:26the study first started enrolling
36:28in two thousand fourteen.
36:31Control of diabetes and lifestyle
36:33choices such as tobacco use,
36:35were monitored, and telephonic counseling
36:37was actually provided to all
36:38patients,
36:40for these purposes.
36:42Medications were provided free of
36:43charge, and this included Repatha
36:45after I was approved and
36:47available in two thousand and
36:48eighteen.
36:52The primary outcome here was
36:53a four year, composite of
36:55any stroke or death from
36:56randomization to forty four days,
36:58which was considered the periprocedural
37:00period for the study,
37:01as well as ipsilateral ischemic
37:03stroke after forty four days.
37:06The secondary outcome included the
37:08primary composite plus contralateral stroke
37:10in the peri in the
37:11postprocedural
37:12period, so after forty four
37:13days.
37:14All strokes here were defined
37:16using the WHO classification. So,
37:18rapidly evolving clinical signs of
37:20focal global disturbance, a perfusion
37:22lasting more than twenty four
37:23hours with no apparent cause
37:25other than vascular.
37:26There was a stroke adjudication
37:28committee,
37:29that further determined if these
37:30were major strokes based on
37:31an
37:32NIHSS, SS scale score of
37:35six or higher, and if
37:36they were disabling strokes based
37:38on the modified ranking score
37:39of three or higher.
37:41There were some additional secondary
37:43outcomes that I didn't didn't
37:44focus on for the purposes
37:45of this talk, and these
37:46specifically,
37:49looked at differences between medical
37:50therapy and revascularization
37:52using a different,
37:53definition of stroke, specifically a
37:55tissue based definition.
37:56So strokes that were found,
37:58by imaging. So those that
38:00may not have been picked
38:00up, clinically.
38:03It's worth noting that results
38:04were the same regardless of
38:05which definition were used.
38:08The study was analyzed as
38:09intention to treat. Kaplan Meier
38:11curves were derived to estimate
38:13event rates, and treatment differences
38:15were tested using a rerandomization
38:17test, to account for the
38:18low expected event rate.
38:23So with regards to the
38:24results, here is, the CONSORT
38:26diagrams for the carotid stenting
38:28study.
38:29Overall,
38:30there were one thousand two
38:31hundred and forty five patients
38:32that were randomized
38:34in this particular study.
38:36Six hundred and twenty nine
38:36were randomized to medical therapy,
38:38and six hundred and sixteen
38:39were randomized,
38:41to carotid stenting, of which
38:42five hundred and seventy five
38:43actually received,
38:45carotid stent.
38:47It's worth noting that there
38:48were a hundred and six
38:49crossovers from the medical arm,
38:51to revascularization.
38:54Of note, there were no
38:55patients lost to follow-up regardless
38:57of what arm they were
38:58randomized to. And the median
39:00follow-up here in the carotid
39:01artery stenting,
39:02trial was four years.
39:05In the, endarterectomy
39:07study, there were, one thousand
39:09two hundred and forty patients
39:10who were randomized.
39:11Six hundred and twenty three
39:12were randomized to medical therapy
39:14alone, and six hundred and
39:15seventeen were randomized to endarterectomy
39:17with five hundred ninety three
39:18actually undergoing the procedure. And
39:20There was a similarly high
39:21rate of crossover,
39:23here with a hundred and
39:24eleven crossing over from the
39:26medical arm to intervention.
39:28And, again, there were no
39:29patients lost to follow-up. And
39:30the median follow-up for these,
39:32for the patients in the
39:33end arterectomy study was three
39:34point six years.
39:38Given the high crossover rate,
39:39and I expect many questions
39:40surrounding that,
39:42I've included a breakdown here
39:43of the reason for,
39:45crossover from the medical arm,
39:47into the intervention arm for
39:48both of the studies.
39:50The most common reason for
39:51crossover in each of the,
39:53studies was either the development
39:55of symptoms that didn't meet
39:56the primary composite, so, TIA,
39:58for example,
40:00or progression of the target
40:01lesion, which accounted, in both
40:03studies for approximately eighty five
40:05percent of the crossovers.
40:07In other instances, there were,
40:09investigator errors,
40:11where the wrong procedure
40:12the wrong randomization,
40:15method was done,
40:16or patients were revascularized at
40:18an outside institution, for example.
40:23Here are the baseline characteristics
40:25for the two studies. It
40:26was well balanced,
40:27overall in all four arms.
40:30Patients were around, seventy years
40:32of age,
40:33predominantly male, predominantly white. Most
40:35patients had hypertension and hyperlipidemia,
40:37and approximately half had coronary
40:39disease and worse current smokers.
40:41About one in three had
40:42diabetes, and one in three
40:43patients had a peak systolic
40:45velocities that were greater than
40:46three hundred and eighty nine
40:47centimeters per second, which roughly
40:49corresponds to stenosis of about
40:50eighty percent.
40:52And,
40:53an additional, one in three
40:54had at least moderate contralateral
40:56carotid disease.
40:58It's worth noting, that,
41:00with regards to,
41:02procedural choices, this was largely
41:04left to the operators.
41:06The only stipulation,
41:07was that for the, anyone
41:09that was undergoing carotid stenting,
41:11everyone had to receive embolic
41:12protection.
41:16With regards to the primary
41:18composite out,
41:20for your outcome, here are
41:21the Kaplan Meier curves, that
41:23are, provided.
41:24For the carotid stenting trial,
41:26the event rate in the
41:27medical therapy arm was six
41:28percent. It was two point
41:29eight percent in the stenting
41:30arm, which was statistically significant
41:32with a p value of
41:33point o two.
41:35This amounts to an absolute
41:36risk, difference of three point
41:38two percent,
41:39which corresponds to a number
41:40needed to treat of thirty
41:42one patients.
41:44While there was a numerical
41:45trend towards better outcomes, with
41:47endarterectomy,
41:47this did not meet statistical
41:49significance,
41:50when compared to intensive medical
41:51therapy alone.
41:54I've also highlighted the, later
41:56portions of the curves here,
41:58which showed a relatively late
41:59change in event rates between
42:01the endarterectomy
42:01and stenting arms,
42:03which were accounted for by,
42:04I think, seven or eight,
42:06post procedural ellipso lateral ischemic
42:08strokes in the endarterectomy
42:09arm.
42:12For those who are more
42:13numerically inclined,
42:14this show this chart shows
42:15the event rates for the
42:16primary outcome as well as
42:17a breakdown of peri and
42:19post procedural outcomes.
42:22Patients who, received medical therapy
42:24alone, were more than twice
42:25as likely to have a
42:26primary outcome event in four
42:27years compared to those, who
42:29underwent stenting.
42:31On the bottom portion of
42:31this chart, you can see
42:32this breakdown of periprocedural and
42:34postprocedural
42:35events. Patients receiving medical therapy
42:37were four times more likely
42:38to have a postprocedural ipsilateral
42:39stroke,
42:40than those receiving a carotid
42:41stent, and over two times
42:43more likely, than patients undergoing,
42:45carotid endarterectomy.
42:48I didn't include it here
42:49as a separate, slide, but
42:51the trialist also did,
42:53an interesting analysis called a
42:54tipping point analysis,
42:56which looked at the number
42:57of events that would be
42:59needed,
43:00that would need to happen
43:01for the stenting arm to
43:02no longer meet statistical significance
43:04or for the endarterectomy,
43:06arm to be, positive.
43:08And tipping point analysis in
43:10the carotid stenting trial showed
43:11that,
43:12three less events in the
43:13medical therapy arm or three
43:15more events in the carotid
43:16stenting arm would be required
43:17before significance was lost. And
43:19then similar analysis in the
43:20endarterectomy
43:21trial showed that seven more,
43:23events in the medical therapy
43:25arm or five less events,
43:27in the endarterectomy arm, would
43:28be needed to,
43:30make, this a positive study.
43:34It's a little bit difficult
43:35to see here, and I
43:36apologize for this. But the
43:38trial is,
43:39prespecified several groups to be
43:41further analyzed in subgroup analysis.
43:43This is a forest plot,
43:46of those subgroups,
43:48which could potentially be hypothesis
43:49generating in the future.
43:51Specifically in the stenting study,
43:54absence of hyperlipidemia,
43:55no prior symptoms, lifelong,
43:59and,
44:00more severe stenosis, which was,
44:02denoted here by a peak
44:03systolic velocity of, greater than
44:06or equal to three hundred
44:07and forty two centimeters per
44:08second. Remember, that's probably
44:10roughly around seventy five to
44:11eighty percent on a duplex,
44:14maybe subgroups,
44:15that benefit more from stenting
44:17than others.
44:20And at this point, I
44:21think one of the questions
44:22that's probably crossing your mind
44:24is how good was the
44:25intensive medical management,
44:27in the patients in this
44:28study.
44:30The answer to that is
44:31better, but not fantastic.
44:34Included here are graphs showing
44:36the proportion of patients that
44:37met prespecified targets for risk
44:39factor modification over time.
44:42On the y axis in
44:43each of these,
44:45in each of these tiles,
44:46is the proportion of patients
44:47that are at the target
44:48range, and the x axis
44:50is time.
44:51Tiles a and b show
44:52the portion of patients who
44:53met systolic blood pressure goals
44:55and LDL goals respectively in
44:57the stenting trial with the
44:58stenting arm represented by the
45:00blue line and the medical
45:01therapy alone represented by gray.
45:03You could see they roughly
45:04correspond to each other.
45:06You can see,
45:08started a little under probably
45:10about fifty percent at target
45:11range for systolic blood pressure
45:13and as well for, LDL
45:14cholesterol,
45:15which improved to about sixty
45:17to seventy percent, by the
45:18end of the trial.
45:20This was, similar in the
45:22endarterectomy
45:23trial, which is included,
45:26in the systolic blood pressure,
45:27and LDL graphs included here,
45:29in tiles c and d.
45:32I did not include the
45:33plots, for other risk factors
45:34like diabetes and obesity, which
45:36are included in the supplemental
45:37material
45:38in the New England Journal,
45:44those, risk factors
45:45require sort of a multidisciplinary
45:47approach and are a little
45:48bit more difficult to manage,
45:49the changes from baseline, the
45:51proportion of patients that met
45:52goal were less so than,
45:55was experienced in systolic blood
45:56pressure goals and LDL cholesterol.
46:00And to provide,
46:02some perspective,
46:04I've included a breakdown of
46:05numbers needed to treat to
46:06prevent stroke,
46:08but been demonstrated in some
46:09of the stroke literature to
46:10date,
46:11to give,
46:13some magnitude,
46:14for the effect that was
46:15shown in this particular trial.
46:17You can see here that,
46:20closure of PFO to prevent
46:21a cryptogenic stroke at five
46:22years, for example, had a
46:24number needed to treat at
46:25twenty nine, whereas our study
46:26showed a number needed to
46:27treat for stenting of thirty
46:28one in asymptomatic
46:30patients.
46:31And some of the medical
46:32management,
46:33had much higher numbers needed
46:35to treat, so adding semaglutide
46:37or aspirin,
46:39or statin,
46:41took a lot more patients
46:42in order to,
46:43hit that goal.
46:46So, in summary,
46:48in patients without out recent
46:49symptoms and appropriate anatomy, the
46:51addition of stenting to intensive
46:52medical management led to a
46:53lower risk of a composite
46:55of perioperative stroke or death
46:56plus ipsilateral stroke at four
46:58years in patients with severe
46:59asymptomatic carotid stenosis
47:01when stenting was performed by
47:03an experienced operator.
47:04Similar benefits were not observed,
47:06for carotid endarterectomy.
47:08There's more to come as
47:09well. I think, there's a
47:11long term post trial follow-up,
47:13study that's being conducted to
47:14evaluate the longer term effects
47:16of further out from four
47:17years, which is what they
47:18did in CREST the initial
47:20CREST trial.
47:21And then CREST h,
47:23is a trial that was
47:24run-in parallel,
47:25to CREST two.
47:27And this, trial looked at,
47:29defect of revascularization,
47:30both stenting endarterectomy
47:32on hemodynamically
47:34significant asymptomatic carotid stenosis on
47:37cognitive decline. So was there
47:38any, improvement in cognitive function
47:40with revascularization?
47:42And that will hopefully be
47:43publishing results soon in the
47:45next couple of months.
47:48So to go back to
47:49our patient,
47:51so after a shared, shared
47:53decision making and discussion, patient
47:55was enrolled in CREST two
47:56and randomized,
47:57to the, intensive medical therapy
47:59arm,
48:00and underwent,
48:02optimization of his risk factors.
48:04However, four years later, he
48:06came back to the emergency
48:07department, or he came to
48:08the emergency department ten minutes
48:09of sudden onset slurred speech.
48:12He had,
48:14by the time that he
48:15had presented to the ED,
48:16his symptoms had resolved. But
48:18on further history taking,
48:19he he noted that he
48:20had a similar episode six
48:21months prior.
48:23His exam had, no focal
48:25neurologic deficits. A A stroke
48:27code was activated at that
48:28point in time,
48:29and an MRI brain,
48:32showed no acute infarct.
48:34CTA head and neck showed
48:35that there was an eighty
48:36to ninety percent stenosis in
48:37his left internal carotid.
48:42And given his potential new
48:44TIA,
48:45after,
48:46multidisciplinary
48:47discussion and,
48:49shared decision making, the patient
48:50under
48:51elected to undergo transfemoral carotid
48:53stenting.
48:54So he would be considered
48:55one of the crossover patients,
48:57for the CREST two trial.
48:59We chose to pursue stenting
49:00given his relatively young age.
49:02Typically, as Lindsay mentioned, patients
49:04that are younger have anatomy
49:05that's better suited for stenting,
49:07specifically their arch and less
49:09tortuosity,
49:10and his history of prior
49:11neck radiation, which made it
49:12would have made him a
49:13more challenging surgical candidate.
49:16Given that he just had
49:17an event, we proceeded we
49:18opted to proceed with both,
49:20proximal and distal embolic protection.
49:22So for those that are
49:23a little less familiar with
49:24it, distal embolic protection involves
49:26placing a removable filter
49:28distal to the lesion,
49:29to catch debris that may
49:30be dislodged during the procedure.
49:32And proximal embolic protection involves
49:34inflating balloons in both the
49:36Why am I so sad?
49:38One.
49:43Station. Thank you,
49:45included here
49:46quickly, I can get it
49:47to replay, is a
49:49Okay.
49:50An aortic arch angiogram, which
49:53essentially is used to evaluate
49:54the aortic arch whether or
49:55not it's suitable for proceeding
49:57with stenting,
49:58in which case this was.
49:59It's a type two arch.
50:02And here are the selective
50:04angiograms of the internal carotid,
50:05which demonstrates
50:07severe stenosis,
50:09which you guys
50:11see here,
50:12just after the bifurcation of
50:14the common carotid.
50:16Awesome.
50:20This is a still image
50:22of the predilation
50:23balloon going up. So I've
50:24labeled everything here. It may
50:25be a little difficult to
50:26see. So at the top
50:27of the screen is the
50:28distal embolic protection device, which
50:30was a a nav six.
50:32The predilation balloon,
50:34is,
50:35below that,
50:36to the right. And then
50:37to the left, the two
50:38balloons that are inflated
50:40are the balloons for the
50:40proximal embolic protection device. So
50:42the top one's in the
50:43external carotid and the bottom
50:45one is in the common.
50:49And then, the stent here's
50:51the stent being positioned.
51:00And then
51:02an angiogram
51:03of the final result, which
51:04is excellent.
51:11So he had no persistent,
51:13focal no persistent neurologic deficits.
51:16He presented to clinic on
51:17follow-up doing well,
51:19and he had a follow-up
51:20ultrasound, which showed up Hayden
51:21stent with no elevated velocities
51:23within the stent.
51:30At this point, I think
51:31we'd be happy to take
51:32any questions,
51:33open it up for discussion.
51:40Thanks.
51:41So before we go into
51:42the questions, I just wanna
51:43highlight a few things. So
51:44this is a prime example
51:46of what we can do,
51:47Yale cardiovascular
51:49section.
51:50This is a trial that
51:51I got involved since the
51:52inception in twenty fourteen,
51:55and it was
51:56a herculean
51:57effort. We enroll over ninety
51:59patients.
51:59And if you follow the
52:01presentation,
52:01there were, zero patients lost
52:04to follow-up,
52:05over nine thousand visits in
52:07the trial,
52:09and it's pretty much unheard
52:10of. The medical therapy that
52:12was offered was as good
52:14as you ever see in
52:15any crowded revascularization
52:17trial.
52:18Our research group,
52:20did an amazing
52:21job supporting it. Our staff,
52:24administrative staff, our nursing staff
52:26was terrific, allowing us to
52:27do that.
52:29Chris h that, Jake mentioned,
52:31can't really talk too much
52:32about it, but is an
52:33incredibly
52:34important study that we'll present
52:36in the next month or
52:37so,
52:38and I will encourage you
52:39to pay attention to that.
52:40With that, questions?
52:43Arden, I think since parenting
52:44was mentioned, I think it's
52:46an opportunity,
52:47for me to reflect not
52:48only on biological parents, but
52:50on intellectual
52:52parenting,
52:53and how proud we are
52:55of,
52:56of both Lindsay and Jake
52:57and what they've accomplished in
52:59their many years here. For
53:00me, it's a little bit
53:01of a reflection because I
53:02was in the room when
53:03we selected
53:04these candidates for our fellowship
53:06and, probably the first group
53:09now that we've been able
53:10to take through,
53:11not only cardiology
53:13fellowship,
53:15advanced clinical training,
53:17advanced research training in our
53:19t thirty twos,
53:21and,
53:22positioning them for what I
53:23think is gonna be a
53:24fantastic career. So congratulations,
53:26to you.
53:27Thanks to Jeff,
53:30for the the t thirty
53:31two program and and for
53:33Donna,
53:34to help with me to
53:35to really be able to
53:36build out these t thirty
53:37two programs to support folks
53:38like you in the future
53:40and, of course,
53:41tremendous
53:42work by both doctors, professors
53:44now, Smoldering, and then, in
53:46in positioning you for for
53:48future success. So congratulations, and
53:49let's get one.
53:55So my questions, and I'll
53:56start. I'm sure there's others.
53:57So,
53:58I think, appropriately, you presented
54:00the intention to treat analyses,
54:01but I'm very interested if
54:02you could speak to,
54:04your interpretation of the as
54:06treated or per protocol
54:09analyses that may be available,
54:10or I can't remember reading
54:12through it, myself,
54:14and, you know,
54:16how those might differ and
54:17and what,
54:18what likely happens when you
54:19do those kinds of analyses
54:21and how they relate to
54:22the intention to treat analysis?
54:23That's my first question I
54:25have a follow-up to.
54:27Yeah. So, unfortunately, there isn't
54:29an available protocol that was
54:30published with the New England
54:31Journal, so I can't speak
54:32to that specifically. But I
54:33can tell you, I would
54:35probably expect this study to
54:36be,
54:38given that there was an
54:39absolute difference that was shown
54:40in the stenting arm and
54:42a significant amount amount that
54:43crossed over from medical management,
54:45I may actually expect it
54:46to be more positive. And
54:47the end, artery acne may
54:48wind up being positive as
54:50a result of that on
54:51a per per protocol basis.
54:54I mean, the intention intention
54:55to treat, obviously, is standard
54:57to do it, but,
54:59would be what I would
55:00like to do.
55:01Yeah. I think if you're
55:02if that relates to the
55:03fact that when you do
55:04these comparative effectiveness strategy trials,
55:06you have to, you know,
55:08realize that the trial is,
55:10you know,
55:12unlikely to be replicated in
55:14real practice,
55:15exactly. So it'll be important
55:17to follow that. I'm not
55:17surprised they held that for
55:18another paper. I'm kinda surprised
55:20the New England Journal didn't
55:21make and put it in
55:21there, but whatever.
55:23The next question is and
55:25it also just allows me
55:26to highlight,
55:27what Carlos mentioned about the
55:29importance for clinical trials programs
55:31and and how everything starts
55:32with a fantastic clinical program
55:34that allows us to enroll
55:35into trials, but also what
55:37we bring here at an
55:38institution. So that protective,
55:40lymphatic protection device is something
55:42I know that our groups
55:43here and particularly Alexandra and
55:45her team over the years
55:46in different roles have advanced,
55:48as a opportunity. Can you
55:50speak, Lindsay, to whether that
55:52was available in the prior
55:53trials, and what is your
55:55interpretation of the impact of,
55:57it's hard to that wasn't
55:58tested, but, the impact of
56:00those devices
56:01in the results you you
56:03shared? Yeah. I think especially
56:04we look back at, CREST
56:05one and other earlier studies,
56:07embolic protection was not routinely
56:08used consistently throughout the earlier
56:10trials, which limits some of
56:11our ability to judge how
56:13significant the periprocedural
56:14stroke risk is for
56:16stenting. I will say not
56:17only has the technology of
56:19the stents advanced, but the
56:20embolic protection, and also, like,
56:21we high highlighted the experience
56:23of the operators. And I
56:24think those three factors have
56:25overall made carotid stenting a
56:26significantly safer procedure.
56:29I'll expand a little bit
56:30on that. So
56:32I think that the Achilles
56:33tendon of carotid stenting is
56:35the use or the ability
56:36to use symbolic protection device
56:38to the point that if
56:39you are unable to do
56:40it, you shouldn't do a
56:41product stand.
56:43Whatever mechanism you wanna use,
56:44proximal distal. I tend to
56:46believe that the proximal protection
56:48give you more ability to
56:50protect the brain during these
56:51procedures, but there are some
56:52other technical challenges with it.
56:54Raul,
56:55so you're the surgeon, and
56:57I purposely invited you.
57:00We've been
57:04we've been
57:05no. You and I, but
57:06our specialties have been at
57:08war with this issue of
57:09which one is better, carotid
57:10stenting versus endarterectomy.
57:13And now we have this,
57:14and everybody's been waiting.
57:16It was purposely presented in
57:17a surgical meeting.
57:19So I would love to
57:20hear your thoughts about
57:22how this trial may change
57:24the way the surgical community
57:26would see their vascularization
57:27strategies.
57:28Thank you. Thank you, Carlos.
57:29First of all, I wanna
57:30take a little exception. I
57:31don't think at war
57:34is well, I I I
57:35I do have to say
57:36there are vascular surgeons that
57:38do carotid stenting as well.
57:39Just but,
57:41I think first of all,
57:43this does establish carotid stenting
57:45as a viable and durable
57:46option. I think we've always
57:48known that once a stent
57:49is in,
57:50it has long term durability
57:52and and stroke protection. It
57:54was all about the initial
57:55stroke risk. And I think
57:57as you,
57:59the the specialty has gotten
58:00better at that initial procedure,
58:03The outcomes have improved, and
58:04I think that's really what
58:06we find.
58:07The the one minor concern
58:08I have is it does
58:09look like you're talking about
58:11two or three events
58:12after three years. If you
58:14look at all the lines,
58:15they all look very similar
58:17to what we've seen before.
58:18Basically,
58:19once you have the stent
58:20in, once you get past
58:21the periprocedural
58:22issues, everything looks about the
58:24same, and so they're both
58:26very viable,
58:27alternatives.
58:28My one concern is that
58:29that you have three late
58:30events in the carotid endarterectomy
58:32group that seem to affect
58:35the statistics significantly.
58:36And so I'd like to
58:37learn a little bit more
58:38about that. On the other
58:39hand, I think the data
58:41are solid, and I
58:43I I think that they
58:44are practice
58:45changing, and I think they
58:46are gonna make a big,
58:48difference for our patients.
58:50Thank you, Raul. Reshma, you
58:51are in the back.
58:53Doctor Nerula is one of
58:54our stroke neurologists.
58:56So you've seen this data,
58:58and, obviously, you get to
58:59see these patients day in
59:00and day out. So now
59:02a patient who is asymptomatic
59:03that traditionally,
59:05we've been conservative,
59:08in our stroke neurology clinic.
59:09I guess I pushed them
59:10a little bit more in
59:11the aggressive side. So what
59:13is your take on this?
59:14What do you tell to
59:15your patients?
59:28So congratulations.
59:29But,
59:30I think scenting is definitely
59:32a reasonable option for people
59:33with high grade stenosis, and
59:35that's something that we have
59:36to present to our patients
59:38now. I think as you
59:40alluded to, the cognitive information
59:42is going to be really
59:43interesting because
59:45if you look at the
59:45baseline cognitive assessment of the
59:47patients, it was worse than
59:49the general population. So I
59:51think
59:51CREST h, which is being
59:53presented at ISC in February,
59:54is going to be really
59:56interesting.
59:57But it's definitely something we
59:58have to present to our
59:59patients now, and I think
01:00:00people who especially have a
01:00:02rapid progression of stenosis on
01:00:04serial imaging,
01:00:06scenting is going to be
01:00:07an option for them.
01:00:09I do wanna highlight the
01:00:11limitations of the trial,
01:00:13and there are some limitations.
01:00:14Jake alluded to them. First
01:00:16of
01:00:17all, you know, the medical
01:00:18therapy used and the ability
01:00:20to achieve their targets,
01:00:21is not what we see
01:00:23in real life. So we
01:00:24have to take that with
01:00:25a grain of salt.
01:00:26Second,
01:00:27although I would love to
01:00:28say that everybody should get
01:00:29a stent, I don't necessarily
01:00:30think that that's the case.
01:00:32I think,
01:00:33two things to that,
01:00:34point. One,
01:00:36the operators
01:00:37really were the best centers
01:00:38in the world,
01:00:40that participate in this clinical
01:00:42trial. And I think it
01:00:42makes a difference in terms
01:00:43of the decision making, what
01:00:45lesion to stand, which lesion
01:00:47not to stand, and what
01:00:48technique and equipment to use.
01:00:50It makes a huge deal
01:00:51of difference.
01:00:53And then last but not
01:00:54least, I think that what
01:00:55we did here at Yale,
01:00:58I think it proved to
01:00:59be, a good practice and
01:01:01is that we focus
01:01:03the
01:01:03or credits stem program
01:01:06such that few operators,
01:01:09were able to perform it
01:01:10given the fact that the
01:01:11volume is at.
01:01:12So
01:01:14it definitely
01:01:15highlighted the effort the conscious
01:01:17effort that was made to
01:01:18centralize our product stem program
01:01:20was the right thing to
01:01:21do and, certainly,
01:01:22it's become,
01:01:24if not the best, one
01:01:25of the best STEM programs
01:01:26in the country.
01:01:27Carlos, so John. I wanna
01:01:29ask two things. One, the
01:01:30only,
01:01:32privilege that I've ever given
01:01:33up here at YEAH was
01:01:34my crowd distancing privilege because
01:01:36I strongly agree with your
01:01:37your last statement there that
01:01:39it needs to be done
01:01:40by experts. And I think
01:01:42when, you know, Jake's initial
01:01:43slide showing the number of
01:01:44people who applied to do
01:01:46it and who were rejected,
01:01:47and that is very hard
01:01:49to translate into
01:01:51actual clinical practice when something
01:01:52gets approved, but I think
01:01:53it's critically, critically important. The
01:01:55other thing that I you
01:01:56know,
01:01:57the, you know, industry it's
01:01:59an industry sponsored study, and
01:02:00they tweak it a little
01:02:02bit to make it and
01:02:03to get a few things
01:02:04in their favor. And I
01:02:04think the the thing that
01:02:05I found
01:02:06most interesting is that you're
01:02:08stenting somebody to prevent stroke,
01:02:10period. But this study didn't
01:02:11look at this. This study
01:02:12looked at stenting to present
01:02:14stroke in the
01:02:17right in the on the
01:02:17other side. But everybody's being
01:02:19put on aspirin and Plavix
01:02:21who gets a stent, and
01:02:22we know aspirin and Plavix
01:02:23is gonna increase your risk
01:02:24of potentially having events. And
01:02:26in fact, if you then
01:02:27look at all stroke that
01:02:29occurred and not just on
01:02:30the side that would have
01:02:31been impacted,
01:02:32that goes that statistical difference
01:02:35goes away.
01:02:37Presumably because there actually tended
01:02:39to be a little bit
01:02:39more strokes on the other
01:02:41side that occurred in the
01:02:43group that got stented or
01:02:44got
01:02:45got, a carotid endartime. And
01:02:47so I'm wondering how you
01:02:48balance that piece because, you
01:02:50know, we we often know,
01:02:51you know, if if carotid
01:02:53stenting didn't have a procedurally
01:02:55related stroke to it, right,
01:02:56the it would be an
01:02:57amazing curve. Right? But there
01:02:58is that one percent there
01:02:59is that procedurally related stroke.
01:03:01And so it really takes
01:03:02a year and a half
01:03:03before your curves cross. So
01:03:04for the first year, the
01:03:06patients who got a stent
01:03:07actually do worse than the
01:03:09patients who didn't get a
01:03:10stent, but then over four
01:03:11years, they benefit. But you
01:03:12have that other part. So
01:03:13I I'm curious sort of
01:03:14how that
01:03:16conversation
01:03:17takes place with patients, both
01:03:19sort of talking overall. Right?
01:03:21Because overall stroke didn't decrease.
01:03:22It was the same side
01:03:24stroke and the procedural rest.
01:03:25Well, just remember, we're testing
01:03:27ipsilateral stroke, no controlateral stroke.
01:03:29Right. And,
01:03:31your point is well taken.
01:03:32I think that one of
01:03:33the hardest things for me
01:03:35to do this trial
01:03:36was to enroll patients. And
01:03:38even though it was so
01:03:39difficult, we were very successful.
01:03:41And it was very difficult
01:03:42because
01:03:43of what you just said.
01:03:44You're talking to a patient
01:03:45who, to begin with, has
01:03:46a low risk,
01:03:48to have an event, and
01:03:49now you're offering a procedure
01:03:50that could potentially increase that.
01:03:53This is why the selection
01:03:54criteria to be part of
01:03:55the trial was such that
01:03:57unless you were able to
01:03:58prove that your event rate
01:03:59was very low, you wouldn't
01:04:00be able to participate on
01:04:02that. So your point is
01:04:03well taken. Shared decision making
01:04:04in this particular pathology,
01:04:07is critical. You see, some
01:04:09of the patients that crossover
01:04:10was because they
01:04:12choose to crossover. They just
01:04:14don't wanna deal. And you
01:04:15see with the you see
01:04:15them in clinic, and they
01:04:17say, well, I'm dying. You
01:04:18gotta fix it. And you
01:04:20you try to convince them
01:04:21that that's not the case,
01:04:22which is, you know, you
01:04:23see that this is not
01:04:25a ticking bomb. This patient
01:04:26is not gonna have a
01:04:27stroke right away, that you
01:04:28have time. The medical therapy
01:04:30is incredibly good,
01:04:32and that the event rate
01:04:33is very low. So
01:04:35it's a good point.
01:04:38Erica Can I ask question
01:04:39online?
01:04:40Okay. Great. Because then we
01:04:41get to end on medical
01:04:42therapy. Okay.
01:04:46They're kind of a related
01:04:47point. One is that I,
01:04:51I can't believe that the
01:04:52smoking
01:04:53rates were so high that,
01:04:55like, nearly half the population
01:04:57were smokers,
01:04:58which seems, like, incredible to
01:05:00me. So I do have
01:05:01a question on whether,
01:05:03you know, smoking cessation, which
01:05:04is still part of optimal
01:05:06medical therapy, was instituted and
01:05:08if that differed between the
01:05:09two groups because it seems
01:05:10like such an important risk
01:05:12factor.
01:05:13And it sort of relates
01:05:14to the biology because
01:05:16you either have an unstable
01:05:18plaque,
01:05:19an embolization,
01:05:20or you have a hemodynamically
01:05:22significant lesion.
01:05:25And medical therapy can stabilize
01:05:28those plaques,
01:05:29we think, and maybe even
01:05:31more aggressive medical therapy than
01:05:33what the trial
01:05:34did. Right? Because our targets
01:05:36have gone even lower for
01:05:37those patients.
01:05:40But the hemodynamic
01:05:42significance
01:05:43is something that, you know,
01:05:45we don't know. And we
01:05:46kinda think, like, the Circle
01:05:47of Willis is kind of
01:05:48gonna be protective, but it
01:05:49kinda gets to to John's
01:05:51point, which is, like,
01:05:52is there more investigation
01:05:54into the mechanism? Because it
01:05:56seems like,
01:05:57potentially, we could be more
01:05:59personalized in our approach that
01:06:00there's heterogeneity
01:06:02within those
01:06:04two arms and that maybe
01:06:06we could better decide who
01:06:07would need a who would
01:06:08need a stent versus who
01:06:10wouldn't, you know, if we
01:06:11have more
01:06:13plaque characterization,
01:06:15more understanding of hemodynamic significance
01:06:17as it relates to brain
01:06:19perfusion.
01:06:19Yeah. I think that's a
01:06:20really great point, and that's
01:06:21something that they're going to
01:06:22look into in secondary outcomes
01:06:24as well. Because right now,
01:06:24essentially, we're treating percent stenosis.
01:06:26We're just treating a number.
01:06:27And there's so much more
01:06:29that goes into, like, what
01:06:29you're saying, plaque characteristics,
01:06:31which of these plaques is
01:06:32likely to rupture. It's really
01:06:34just independent of the, you
01:06:35know, diameter itself. So if
01:06:37we have better mechanisms to
01:06:38enhance our imaging or find
01:06:40some way to determine which
01:06:42plaques are more vulnerable, that
01:06:43would be helpful. They are
01:06:44doing a secondary analysis where
01:06:46they do have angiographic
01:06:47images and CT images at
01:06:49baseline
01:06:50and, for folks who did
01:06:51undergo strokes so they could
01:06:52try to compare and draw
01:06:53some conclusions
01:06:56worried about in terms of
01:06:57plaque characteristics and who is
01:06:58more likely to have a
01:06:59stroke versus just looking at
01:07:01the number of their stenosis.
01:07:02Yeah. So all the asymptomatic
01:07:04patients are not the same.
01:07:05Yeah. They are very heterogeneous
01:07:07in nature. So the imaging
01:07:08component that Lindsay just mentioned,
01:07:10will help us to characterize.
01:07:12Moran has done research,
01:07:14to try to define and
01:07:15characterize the nature of the
01:07:17plaque, which one is gonna
01:07:18burst, which one is not,
01:07:19that kind of stuff. Chris
01:07:20h, look at your other
01:07:21question,
01:07:23which is from the hemodynamic
01:07:24perspective,
01:07:26which seventy percent is almost
01:07:27the equivalent of an FFR?
01:07:30And
01:07:31which one which lesion is
01:07:32hemodynamically
01:07:33significant
01:07:34and the impact
01:07:35in the event rate,
01:07:37but also in the cognitive
01:07:38function. That to me was
01:07:40the most important part of
01:07:41this trial,
01:07:43but you'll get the results
01:07:44in pepper.
01:07:46Can I ask a question
01:07:47online?
01:08:02Yes.
01:08:03Yes.
01:08:05Yes.
01:08:28Change that or
01:08:30static, but
01:08:33that's one possible.
01:08:35Yeah. So the question to
01:08:36the imaging, yes, there were,
01:08:38extensive imaging modalities done in
01:08:40this patient. So you'll get
01:08:41the answer to that in
01:08:42the next few months.
01:08:44And the cognitive function also,
01:08:46you're gonna have to wait
01:08:46until February.
01:08:47So with that, we thank
01:08:49you very much for coming.
01:08:50Have a good day. Good
01:08:52job, miss. Thank you. Very
01:08:53good. Very proud.
01:08:59Oh, there somewhere. Hey. How
01:09:01are you? Good. How are
01:09:01you? Hi there.
01:09:03Congratulations.
01:09:04Thanks so much.