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Highlights Of The ESVS 2018 Carotid Guidelines: Advice Re Optimal Treatment Of Asymptomatic Patients With Carotid Stenosis (ACS)
Highlights Of The ESVS 2018 Carotid Guidelines: Advice Re Optimal Treatment Of Asymptomatic Patients With Carotid Stenosis (ACS)
Update On Indications For Invasive Treatment Of Carotid Disease (Symptomatic And Asymptomatic) By CEA Or CAS Before Major Surgery Or Coronary Bypass
Update On Indications For Invasive Treatment Of Carotid Disease (Symptomatic And Asymptomatic) By CEA Or CAS Before Major Surgery Or Coronary Bypass
New Subanalysis Findings From The ACT-1 Trial: What It Tells Us About The Treatment Of ACS And What It Does Not Tell Us
New Subanalysis Findings From The ACT-1 Trial: What It Tells Us About The Treatment Of ACS And What It Does Not Tell Us
Abbott Vascularadditiveaggravatedanalysisasymptomaticatheroscleroticburdencarotidcarotid stent systemCASCEAcognizantcomorbiditiescomparedconcordantcoronarydataembolicendarterectomyendpointipsilateraloctogenarianspatientsperipheralrandomizerandomizedriskstandardstentstentingstrokesubgrouptrialvascularweightedXact
Why CREST 2 And ACST 2 May Have Little Definitive Value Although They May Provide Useful Information
Why CREST 2 And ACST 2 May Have Little Definitive Value Although They May Provide Useful Information
Status Of The ECST 2 RCT Comparing CEA Or CAS And BMT To BMT Alone In Symptomatic And ACS Patients: What Will It Tell Us And When
Status Of The ECST 2 RCT Comparing CEA Or CAS And BMT To BMT Alone In Symptomatic And ACS Patients: What Will It Tell Us And When
A New System For Stroke Prediction In ACS Patients: When Is Invasive Treatment (CEA/CAS) Mandatory And Justified
A New System For Stroke Prediction In ACS Patients: When Is Invasive Treatment (CEA/CAS) Mandatory And Justified

- Thank you. Thank you to the Veith for inviting me again for this meeting. So, we're going to deal about optimal treatment of asymptomatic patients with carotid stenosis. I have no financial disclosures. So, the first thing to say about the treatment

of each patient is intensive medical therapy and this has been discussed before. Smoking cessation, low-dose aspirin, statins to maximum tolerated dose, angiotensin converting enzyme inhibitor, and optimal blood pressure control.

Essentially, they are recommendation 1A. But, the adherence to medical therapy has never been evaluated in landmark RCTs and never evaluated for secondary prevention in patient with asymptomatic carotid stenosis. And you see here, in a study by Chen,

that among more than 1000 patient with vascular disease, range of adherence to guideline-recommended therapies at three month was not optimal. It was quite good for aspirin, lower for statins, and even lower for ACEIs. The other thing is that the recommendation for surgery

or any kind of revascularization in the asymptomatic patient with more than 60% carotid stenosis rely on ACAS and ACST trial that are fairly updated. And you see in this column, in the ACAS trial, the rate in the medical arm, the rate of stroke, ipsilateral stroke per year, 2.2%.

In 2004, in ACST first part, it was 1.1% per year, and then, in ACST year six to 10, published in 2010, it was 0.7%. So finally, we added, you know, significantly, the munition of the risk of stroke in the medical arm of nearly 60%.

And this is, in relation, we've arrived at the best medical therapy. Nothing must change for antiplatelet use, but still stable, around 90% of the patient, but you see a rise of antihypertensive drug from 50% to 90%,

and the dramatic rise of lipid-lowering drug from 10% to nearly 80%. And when you see this consequence in ACST-1, the net benefits of carotid endarterectomy were significant both for those on lipid-lowering therapy and for those not.

So, the main idea is that not all asymptomatic patient need a revascularization, but degree of stenosis is not all. In asymptomatic patients, risk of stroke seems for us to be more related to the structure of the plaque than to the degree of stenosis.

And you see, and so we suggest the following clinical and imaging features associated with an increased risk of stroke in these patients with asymptomatic carotid stenosis treated medically. Contralateral TIA stroke with odds ratio three,

cerebral imaging with ipsilateral silent brain infarct, ultrasound imaging with progression of stenosis, spontaneous embolization on TCD, large plaque, echolucent plaque, HITS on TCD plus echolucent plaque, and finally, an MRI intraplaque hemorrhage.

And it has been shown that asymptomatic patients with silent infraction have a higher risk of ipsilateral stroke, 3.6% versus 1%. On the same area, embolic signals on TCD in patient with asymptomatic carotid stenosis are associated with a higher risk of stroke.

So, we end with this recommendation. Carotid stenosis 60 to 99, life expectancy more than five years. One or more than one features that we described suggesting higher risk of stroke, and this is class IIa B.

Calculated B plus, best medical treatment, should be considered. We've a lower recommendation for CAS, maybe can consider it. No indication for string sign with occlusion or near occlusion. We flat out treated with best medical treatment only.

Just a word on carotid endarterectomy versus stenting in the asymptomatic patient. Due to a recent technique of CAS for the familiar approach in asymptomatic patient, CAS is associated with a significantly higher risk of stroke

and death rate at 30 days. So our recommendation is lower. So this recommendation were made by a group of people, 85 authors and reviewers agree with it, on these recommendations, and you can then well subscribe

in the European Journal of Vascular Surgery, or in the European Heart Journal. Thank you.

- Thank you very much Frank and thanks for the invitation. My first thing is to deal with the patient who's awaiting CABG who's had a previous stroke or TIA. This is the only study of it's kind showing that if you proceed with isolated CABG, the risk of stroke is extremely high and if you look at the meta-analysis that we've done of whether you do endarterectomy or

stenting in symptomatic patients, this is all the literature there is. And what you can clearly see is that the death and stroke rates in patients undergoing CAS followed by CABG are much higher than after carotid and endarterectomy. And that lead us to recommend that a stage of

synchronous carotid intervention should be considered in CABG patients with a history of stroke or TIA and who have a 50 to 99% stenosis. But advise that for now, if you're going to do that such an intervention, surgery should probably be considered instead of stenting.

But 96% of all interventions of the CABG and carotid variety are in asymptomatic patients, so what about them? Well, this is all the literature there is on stroke risk in patients undergoing isolated CABG with a unilateral asymptomatic stenosis of 70 to 99 or 80 to 99 and you can see there is an awful lot of zeroes

in that table and if you go at patients with bilateral significant disease, the death and stroke rate is much higher but again there is not too many strokes here. And if you look critically at the literature and ask yourself okay we've had so many strokes, how many of them can be attributable to underlying

carotid disease by looking at the CT scans or the distribution of lesions, you'll see that between 85 and 95% of all strokes cannot be attributed to an underlying significant carotid stenosis. And if you look at all the death and stroke rates and this is a multiple meta-analysis that our

group have done over the last 15 years, these are the death and stroke rates depending on how you treat the patients, and 80% of these are asymptomatic and 80% have got unilateral stenosis and the death and stroke rates are far in excess of the risk of stroke if you just perform an

isolated CABG in patients with unilateral asymptomatic disease. There have been two randomized trials. This is one, the Iluminati trial that Jean-Baptiste was involved in, 30-day death and stroke rates not significantly different.

There is quite an astonishing trial from Germany, which was again unilaterally asymptomatic stenosis with a near 20% death and stroke rate with synchronous carotid CABG and a 10% definite stroke rate with medical therapy, ah isolated CABG, sorry. So the ESVS have advised that a staged synchronous

carotid intervention is not recommended in CABG patients with an asymptomatic unilateral, 70 to 99% stenosis for preventing stroke after CABG. A staged synchronous intervention may be considered in patients with bilateral disease, the evidence is not brilliant but it's such a rare thing that it's

probably not worth arguing about. Now what about patients who are undergoing non-cardiac surgery? This is quite an interesting group, because if say, a gastrectomy, a hip replacement or whatever, if they've had a previous history of stroke or TIA

they should undergo carotid imaging and if they've got a significant stenosis they should undergo prior carotid revascularization prior to undergoing their gastrectomy et cetera. But what about the asymptomatic patient? This is quite interesting.

First of all, let's just look at a very large study by Jorgensen, 4 nearly 500,000 elective non-cardiac operations and 7,000 had suffered a prior stroke or TIA, and the most important thing was, the stroke risk was directly related to the time from the onset of the TIA to doing the operation.

So if you did it within three months of the stroke or TIA there was a 12% peri-operative stroke rate, but if you managed to get out to six months, the stroke rate was only 0.1% so the lesson learned there is that if it's possible to delay surgery in patients who've had a prior stroke or TIA

or a recent one, you should delay it for six months. Only two studies have looked at whether asymptomatic carotid stenosis increased the stroke risk in patients undergoing non-cardiac operations. Ballotta did a randomized trial, and Sonny, which is a very large observational study,

looked at the impact of asymptomatic carotid stenosis on outcome and found that there was no evidence that a pre-existing carotid stenosis increased the risk of stroke in patients undergoing major non-cardiac surgery. Similarly, in a huge study on TAVI patients,

no evidence that carotid disease was a risk factor for perioperative stroke. So in our recommendations we advised routine carotid imaging in asymptomatic patients undergoing major non-cardiac surgery is not recommended and prophylactics and arterial stenting is not

recommended in patients with asymptomatic carotid stenoses undergoing non-cardiac/vascular procedures. And if you'd like to look at all the literature and data that we came to in using to our conclusions, the guidelines are free to access on the internet.

Thank you very much.

- Thanks Mark and Frank for the invitation. This is a subgroup analysis for the ACT one trial. I have conflicts where I've research grants through UW, and Xact carotid stent is off-label for standard risk patients in the US. And the trial ACT one was sponsored by Abbot Vascular. Our original design was

a 3:1 weighted randomization. When you look at the numbers you'll see that weighted randomization. And we did randomize patients after clearing their investigators, both surgical and interventional,

with very stringent criteria. Our primary composite endpoint that we presented before publishing it in a journal was there was not inferiority margin that was met. Our primary endpoint of one year, with 30 day DSMI and ipsilateral stroke.

The subgroup analysis I'm going to show you today is by sex, a very popular one. You might ask why is he presenting age, and it's because our vascular group did not believe that octogenarians the evidence supported asymptomatic intervention attempt

in those patients, so we can't really do a subgroup analysis by age, since we truncated the them out as an exclusion criteria. And then we also looked at atherosclerotic burden as a measure of patients who also

have concomitant known coronary artery or peripheral vascular disease. In the ACT one's gender analysis we're cognizant that in some of the post-hoc analysis with other major trials, women did not show the same benefit,

or actually showed greater risk with carotid intervention. And we with ACT one had the largest randomized trial for stenting with embolic protection on asymptomatic patients. This is the demographics between the two.

Not a lot of significant differences in age or degree of stenosis, hypertension, diabetes or smoking. Also not major differences in other demographics. This is the men, who showed very similar rates at five years of ipsilateral non-perioperative stroke there was no difference.

And in women, there was a difference in ipsilateral late 31 to five years non-perioperative ipsilateral stroke. About 99 and 96%. Why would you look at analysis of atherosclerotic burden? We previously analyzed some of the

carotid stent post market data sets. And found that compared to the literature on open vascular surgery or multiple comorbidities, such as coronary disease and renal failure, have aggravated and even additive risks, more additive as well as aggravated risks.

We found in carotid stenting that the number of comorbidities seemed not to have an impact on peri procedural risks. We wanted to look at this in a larger data set of standard risk patients. And this is a complicated slide,

I'm going to show you the last one in highlight. And that is that if you look at the patients who had a known coronary and peripheral vascular disease, there appeared to be less risk with stenting compared to endarterectomy.

And in this case we included the 30 day DSMI and the late ipsilateral stroke. If you look at ipsilateral stroke only, not including the perioperative. Again, looking at the subset with known coronary and known vascular disease,

there also appeared to be a difference with improved results with stenting compared to endarterectomy. There's several limitations to this. The most important is that these sub analysis were not pre-specified.

These are post-hoc analysis. And all of us who do a lot of trials and look at this data again and again recognize that the weakest or trap of alpha inflation when you do subgroup analysis. So these have to be taken as exploratory only.

In summary, ACT one's the largest randomized trial of standard risk asymptomatic patients comparing stenting and endarterectomy. We did not include octogenarians. The rate of late ipsilateral stroke was lower with stenting than endarterectomy in women.

And the patients with the most atherosclerotic burden with known coronary and known peripheral vascular disease the outcomes appear to be slightly better with stenting than endarterectomy, which is concordant with our findings from Capture two. Thanks for your attention.

- So thanks a lot, Frank. And I think one of the things that you had asked us to highlight was what were the problems we faced so far. So, I'm going to throw that into this. These are my disclosures, they don't present any conflict.

CREST-2 as Dr. Veith referred to are two concurrent two-arm trials, and the primary end point is periprocedural stroke or death plus ipsilateral ischemic stroke up to four years.

So jumping right into the problems. In an environment of low stenting activity nationwide, one of the first things that we encounter, one of the first problems was how do you credential

high-quality interventionists? And you can see this exemplified in this slide. 383 surgeons applied for Carotid Endarterectomy privileges, and I believe Dr. Westmore is in the audience somewhere.

He's a very strict reviewer, and he approved 97% of them. On the other hand, 332 Interventionists have applied and only half of them were approved. And almost half of them

were conditionally approved for a lack of recent Carotid Stenting Activity. And so in response to that, back in 2015, we initiated the CREST-2 Registry, with the goal of helping in the rapid initiation of credentialing

and enrollment in the trial. And how has the registry helped? We've enrolled now 3,800 patients in the registry. Excellent stroke and death outcomes in it, but more importantly,

starting with 31 credentialed interventionists, the registry has successfully enhanced the ability of interventionists to get their numbers up and get credentialed and certified to start enrolling in the trial.

And this is actually exemplified in the activities of our Interventional Management Committee, where in a multi-variable analysis, we found that the number of cases performed per month by interventionists

was the single most important factor in performance quality, specialty, in fact, was not a factor, and these results are about to be published. Enrollment. We're actually doing very well.

We're amongst probably the top 10% of NIH-funded Clinical Trials across the board that are enrolling on target. This graph shows the bars, which are our Enrollment, and the red tops, which are the NIH Mandated Targets.

So we're essentially on target. Our most recently enrolled patient was about 2.5 hours ago, but who's counting? And we're about, we hope, to have half of the patients enrolled by the end of the year.

And both trials are doing well, about 50/50 in each. Second problem. How do you achieve a very ambitious target enrollment of 50% women and 15% minorities

when no other Carotid Trial have ever come even close to those numbers? We've set ourselves very ambitious targets. We're currently sitting at 41% and 13.5% for those two criteria. Life Line Screening is a private organization

that conducts Carotid Screening Programs in about 7,800 zip codes across the country. Last year, they identified over 1,000 individuals with a peak systolic velocity in their Carotid territory, in their Screening's Carotid territories,

just in one year. And so we approached NIH and proposed a partnership with Life Line Screening where they would conduct Screening programs around our 153 CREST-2 Centers,

and then refer those patients with their permission to our CREST-2 sites. We've just received funding for it and CREST-L is off to the races, we're hoping that it will help in the enrollment of women and minorities.

Third problem, is asymptomatic carotid stenosis associated with cognitive impairment? We had a whole session this morning, and our data, along with other centers, has shown that Asymptomatic carotid stenosis patients do tend to have impairment.

In fact, 50% of them have at least two domains impaired. And even more interestingly, 80% of those with impaired profusion in the brain had at least one domain impaired. And so, we had in 2017, CREST-H funded,

which is looking at do patients with impaired flow and impaired cognitive function benefit from revascularization versus intensive medical therapy as a strategy? Problem four.

How can you lose this golden opportunity to search for subsets of patients at an inordinately high stroke risk? And so we just recently got word of funding for CREST-M, whose goal is to look at biomechanical forces

as well as plaque morphology as a risk factor for future stroke. And we're going to look at biomechanical forces by measuring strain patterns using cine ultrasonography, and then we're going to use Carotid MRA's

and CT angiograms to measure the morphologic composition of the plaques. Final question. How do we incorporate new technology and new procedures into a flexible type of trial knowing that these kind of trials

take so many years to perform? And we have a proposal in that we hope to get funded and initiated next year called CREST-T that's going to look at the role of Trans carotid revascularization

versus Endarterectomy and Stenting within a subset of patients in the registry, so it'll be a nested randomized trial. So will we have a final answer from these CREST family of studies? We'll certainly hope that it's a last chance

in many years to get a contemporary answer. Thank you all for your attention.

- Thank you very much. I'll try to zip along to make time for discussion. There are two big questions in carotid research. The first is the CREST-2 question, should we now be considering intervention for asymptomatic carotid patients? Well here's the sum total of the randomized evidence

upon which such decisions should be based until we have alternative truths. And this shows that every trial of asymptomatic carotid intervention shows entirely consistent results. A successful procedure halving the risk of a long term stroke.

And I'm sorry Tom Browne isn't here cause I've got a 10 pound bet with him that CREST-2 will be entirely consistent with this meta-analysis, but of course 10 pounds now is worth less than 10 pounds was worth a few days ago. So, yes is the answer to that.

So then because several hundred thousand asymptomatic carotid procedures are done currently each year, a logical next question is how should we intervene on these patients? Should it be surgery, should it be stenting, and that's where ACST-2 comes in.

So ACST-2 is a large simple pragmatic trial and we will randomize 3600 patients in around one year's time. Surgery and stenting in both cases, collaborators are free to use their usual techniques. So if it's surgery we do not mind if it's GA or LA,

primary or patch closure, shunt selectively, shunt routinely For stenting any CE marked stent is allowed in the trial. Whilst we encourage protection, it is not mandated. It's an international trial recruiting across 30 countries. Many of our collaborators are here today and the reason ACST-2 is successful

and will be successful is entirely down to their hard work. So we are recruiting well over one patient per day to match BK's sort of boast, we had four patients last night randomized to the trial. So we will complete recruitment in around one year's time. What sort of patients are we recruiting?

70% are men, so we're not going to meet the gender balance that they're aiming for in CREST. A median age of 69, they're quite comorbid. One third of coronary disease, one third of diabetes, and around one in 10 of renal impairment. They're also quite high risk for stroke.

6% atrial fibrillation, around one third are actually over 75 and one third have a previous stroke symptoms or prior brain infarct on cross sectional brain imaging. Medical treatment at entry to the trial is quite good and better long term.

We're also capturing secular changes in the use of stents and also protection devices. Closed cell stents still predominate but we see the new dual layer stents emerging as popular stenting options within the trial. 15% of our patients are done with cerebral protection

of those who have protection, two thirds have filter and the rest are a mixture of proximal occlusion and distal balloons with the first TCAR was done in ACST-2 a few weeks ago. I don't have unblinded results but the most recent DNC report allowed us to share these data with you.

The rate of disabling and fatal stroke within 30 days of the procedure was 1.0% and that's lower than observed for carotid endarterectomy in ACST-1. Suggesting that these procedures are being done safely in the context of a randomized trial.

So when will we have our results, Dr Veith? Well where are we now with 3100 patients randomized, we'll complete recruitment late 2019, early 2020. We'll then spend a year gathering all the outcome events and report five year results in mid 2021. We also have agreements to pool ACST-2

with the results of CREST-1 asymptomatic cohort, ACT-1 and SPACE-2 and that will give us some IPD meta-analysis of 6000 patients. And with apologies to John, that's the sort of scale of data you need to do meaningful subgroup analyses. We'll then uniquely carry on following or base ACST-2

patients for a further five years via post and then we'll have 10 year results of stenting versus surgery in this cohort mid 2025. And I think around that time, CREST-2, ECST-2, and ACTRIS may also report meaningful long term results. So when I'm in my mid to late 50s all the questions

will be answered, we'll stop having these debates and we'll move forward with evidence based. Thank you very much.

- Thank you. I have no conflict of interest. Now the first burning question in carotid artery disease management. I agree with the previous speaker somewhat. Is that is who if anyone with asystematic Carotid Stenosis is likely to benefit from a carotid procedure

in addition to current optimal medical intervention? Where I have to ask this question because of significant advances in medical revascularization over the last three to four decades. Particularly since ACAS was published.

Now at most about 4% of persons with asystametic cartonied stenosis will have a stroke caused by the lesion as explained on Tuesday. We just know that its overall harmful and wasteful to do a procedure on all of them.

But stoke risk stratification cannot identify those who now benefit from carotid endocardectomy and stenting is overall more harmful than endocardectomy. There are many proposed markers of high stroke risk in asymptomatic carotenosis patients given just medical treatment.

Including those some of the European society vascular surgeons. But we already know that each of these markers used in isolation they lack sufficient specificity to identify those most likely to benefit from a procedure. In other words they are to common.

And also the event rates with these individual markers are too low. Particularly considering that all of these studies of these markers were done with suboptimal medical treatment. The second burning question.

Is will prevailing carotid trails find a current procedural indication in stroke prevention? Well the answer with respect to ACST-2 is no. Because its just a trail of stinted verse endocaretomy There is no medical treatment only arm. So its not testing the efficacy of these procedures.

It will help to measure harm of one procedure versus another. But this is of little value without a procedurual indication in the first place. The answer of CREST-2 is not too. Because unfortunately there randomizing

average risk patients like those in ACAS. And we already know that to do a procedure on all of these people is going to be futile and harmful. There's no stroke risk stratification before recruitment. An although they are doing some sub group analysis with markers.

Are these powered sufficiently? I haven't seen that is the case so far. If you look at the CREST-2 sample size. There is approximately 85% power to detect differences in peri-procedural stroke or death or later ipsilateral stroke with endocardectomy versus stent

or stenting versus medical treatment. If the average annual event rate in the medical intervention arm is greater than 2.1 or less than .2 compared to .9 in those procedural arms. Now we know from CREST-1 that they did achieve and average annual event rate of .9 with endocardectomy

but not with stenting. The risk there was about twice as high at 1.6. And its highly likely that they will get an annual event rate in the medical intervetion arm within that range. So that means that the overall role

CREST is most likely to show that stenting causes harm and endocardrectomy knows significant difference with the respect to medical intervention on its own. In other words no procedural indication because if stenting is more harmful we won't do it. And if endocardectomy adds no benefit we won't do it.

The same response for ESCT-2 because like CREST-2 its randomizing average surgical risk patients. No stroke risk stratification before recruitment. Not pre-powered for high stroke risk markers that we have been talking about. ACTRIS has the best chance of finding a procedural role

in asystematic carotid stenosis because they are doing stroke restratification before recruitment. Using embolize detection, errands of impaired to cerebral vascular reserve, errands of intraplaque hemorrhage on MRI

and errands of rapid and severe stenosis progression. But the outcome of this will depend on how the data is analyzed. For example these markers be tested separtly or combined. We already know that markers individually lack specificity. And at the moment the trail does appear to underpowered

with the total of only 700 total patients expected. Mean while TCAR is being accessed only in registries plus or minus input in CREST-2. So it appears we have absent or underpowered comparisons with current medical intervention.

So a clinical indication is unlikely to be established with the current research that is planned. Actually procedural trails are premature when it comes to asystametic cartonid stenosis. What we should be doing is first defining current optimal medical treatment.

Measuring its impact. Risk stratifying people. Using procedural trials only if we find a sub group with an ipsilateral stroke rate that is high enough despite current optimal medical treatment. So if anyone would like to help on this path.

Please speak to me afterwards.

- Thanks very much Frank and Mumbar, thank you for inviting me to give an update. I like to think of myself as something of a sheep dog rather than a wolf or a sheep. There we are. No disclosures. So, for those of us who are old enough, Frank,

to remember ECST-2 and NASCET trials, these both show benefits of carotid and atherectomy preventing stroke, much to the chagrin of the neurologist who designed the trial, and Peter Rothwell subsequently designed a risk model derived from the ECST data, validated by the NASCET data,

which indicated that only patients with a five year risk of stroke greater than 20 percent benefited from carotid endarterectomy, and I'm not going to go into all the arguments or discussions we just had about asymptomatic patients. And as Anne Abbott has just pointed out to you,

since the original trials, medical treatment has improved for the prevention of stroke and MI because it's the same, really, have evolved and improved, Clopidogrel, and other anti-platelet agents, statins, and other anti-cholesterol agents, better medications for blood pressure control,

and better smoking cessation therapy is making cessation therapy reduction rates. So the hypothesis of the ECST-2 Trial, is that the routine use of modern optimized medical treatment (OMT) in patients with carotid stenosis will halve the risk of recurrent stroke and patients with a predicted risk

of stroke within the next five years of less than 20 percent will not benefit from any intervention, whether it's carotid endarterectomy or CAS. So, how do we calculate the risk of stroke? We use the Carotid Artery Risk score or CAR score, which has been recalibrated to include asymptomatic patients

and the predictive benefit of OMT, and the risk factors used to asses the CAR score are the gender, severity of presenting events, degree of stenosis, plaque morphology, a very crude plaque morphology, but there is some plaque morphology, age, and the time since the last event, and those factors are

put on that colored chart which is available on the website. We use that in our multiple compulsory team meetings, we have a laminated copy for error which is pulled out for every patient to calculate very quickly their CAR score, and this is the trial design.

So, symptomatic or asymptomtic carotid stenosis greater than 50 percent, the CAR score has to be less than 20 percent, to be elegible for ECST-2. If it's greater than 20 percent, then the recommendation is intervention, of course, so all patients coming through MDC really should be eligible for something.

The MRI of brain and carotid or CT, plus ultrasound carotid plaque, and then you can choose, it's a pragmatic trial, just as Richard Bulbulia explained to you about ACST-2, pragmatic trial, you can do a carotid endarterectomy, carotid stent, it's the centers that are approved,

as well as the individual interventionists, and neurologists, and the randomization, is then to optimize medical therapy, plus carotid endarterectomy, or optimize medical therapy, plus carotid stenting, or OMT alone on a one to one basis, follow up for five years, MRI brain at two and five years.

And troponin and ECG at 24 hours post procedure. Primary Outcome Measure, any stroke, any MI or procedural death attributed to carotid revascularization, an MRI or CT brain required for any stroke, ECG and troponin is required for any MI. Progress, we have 32 centers enrolled, 364 patients

randomized to 29th October 2018, the recruitment rate is growing exponentially, and at the moment we're recruiting, over a hundred patients per year, we hope that will double. The number needed for the MRI based safety study is 320. Now this safety study is designed to test the trial design,

trial safety and to also validate the power calculation, which is two thousand patients for the clinical study. Now that we've already recruited that number, so we can reckon we should have the results of the safety study within two years' time. 164 have had MRI plaque imaging, and we need 244

with two years' follow up to look at that analysis, so I reckon it should be three years before we have that data. We do need new centers, as Richard Bulbulia has pointed out, we don't want this to become a historical trial. Ideally, all these trials will be aggregated at the end,

so it's in our interest to recruit as many centers as possible. Please contact us if you're interested. Thank you.

- Thank you Frank for the invitation. Good afternoon. I have no relevant disclosures for this particular talk. So, these RCTs have shown the benefit of doing CEA in patients with asymptomatic carotid stenosis, but the results are really based on very low ARR and a very high NNT.

And, these studies were also conducted when best medical therapy was not as effective as now with now increasing use of statins and newer antiplatelet agents. All those societies kind of concur with the SVS guidelines that in asymptomatic patients with a 60% greater diameter

stenosis should be considered for CEA if the patient has a 3 to 5 year life expectancy and if you can achieve preoperative results of less than 3%. However, this systematic review really sort of concluded that current vascular disease medical intervention is now best for stroke prevention.

So, the controversy continues. So, we decided to look at the natural history of patients with asymptomatic carotid stenosis. So, we identified over 2500 patients with asymptomatic carotid stenosis. We focused on the patient that would be most at risk of

getting possibly a stroke by looking at the ones with an 80% to 99% stenosis. That was based on a carotid duplex showing an end diastolic velocity of 140 cm/sec and greater. We defined asymptomatic as a standard way, no ipsilateral neurologic symptoms in the 6 months prior

to the index duplex ultrasound. Optimal medical therapy was defined as patient either on asprin or clopidogrel and combined with statins. And, unfortunately, in outpatient population only two-thirds of the patients were actually on this best medical therapy.

As you can see after a mean follow up of 1.3 years, we actually had an 11% incidence of ipsilateral neurologic symptoms and most of these were actually stroke, and it was only a single TIA. But, when you look at the risk of INS,

it was 5.8% on those patients on best medical therapy. It was 20.7% on those that were not on optimal medical therapy. We started to look at all the potential risk factors that increased that risk of potentially adding a stroke in those asymptomatic carotid stenosis patients

and found in all the demographics and comorbidities only a single factor was associated with an increased risk of INS, and it was diabetes. When we look at the carotid duplex data and we also did a significant amount of plaque morphology analysis,

actually it was only the ICA/CCA ratio as well as the end diastolic velocity greater than 120 that were significantly associated with that increased risk of having a stroke. And, when we look at the impact of medical therapy, it was either the lack of clopidogrel or

lack of any antiplatelet agent associated again with that increased risk of stroke. So, this univariate analysis showed that these are the five factors that we found associated with an increased risk of ipsilateral neurologic event, but by multivariate regression analysis,

actually only end diastolic velocity greater than 200 was independently associated with an increased risk for ipsilateral TIA or stroke and that odds ratio was significantly high at 15.75. We built an AUROC model to try to build this new predictive model for the risk of stroke in

those asymptomatic patients and that AUROC curve showed that the presence of two or greater risk factors, either diabetes, EDV greater than 200, or the lack of clopidogrel was highly predictive of the risk of stroke as you can see here, and that sensitivity was at 89% and

a very high specificity of 78%. The impact on looking at Kaplan-Meier survival free of stroke, the impact of those two or more risk factors was significant, but the impact of optimal medical therapy actually

was not significant on those Kaplan-Meier survival curves. So in summary, I think every effort should be made to ensure that all patients with asymptomatic carotid stenosis receives optimal medical therapy irrespective of the decision to revascularize or not.

We identified these three risk factors predicting stroke in asymptomatic patients, diabetes, EDV, and the lack of clopidogrel in their medical therapy. So, repair of asymptomatic carotid stenosis in my mind is never mandatory.

However, CEA is often justified if it can be done safely, if a patient has a significant life expectancy, and if you can identify those risk factors that increase their risk. Thank you. (clapping)

- Well again at this session, I'm sure you're all getting tired. I know I'm hearing so much carotid stuff, I'm almost worn out about it. But you've heard some really great talks and we'd like the audience to come up and ask some questions.

I have one concern, I don't even know who to address it to Medical treatment is evolving as we sit here with the PCSK9 inhibitors and the new data, although Sharif may disagree with it,

showing that the lower the LDL, the lower the stroke rate. So, anyone on the panel want to comment on that? Yes? - Frank, the Crest-2 study design was developed to accommodate for these changes. So in November of last year,

the blood pressure recommendations were initiated for review and then a few months ago, the lower limits for what was defined as normal blood pressure was changed by the American Heart Association. We incorporated that into the trial.

PCSK9 inhibitors are also now available free of cost to Crest-2 patients who are not able to achieve their LDL target. - But BK, the problem is you're recruiting, you've recruited half your patients, you're changing the goalposts as you go along.

- Absolutely. So will you have enough patients entered that are treated by best medical treatment at the end of the study, so you can draw a conclusion? I really worry about that and if you come up with a negative result

within a positive result, we'll continue to have these debates. Anyhow... Yes? - (mumbles) makes an interesting comment about the Clopidogrel.

When Jean Baptiste and I and the working group, we're working, both with the ESC and the SVS on the carotid guidelines. There is a real dilemma with anti-platelet therapy, because no randomized trials have showed that anti-platelet therapy reduces stroke

in asymptomatic patients and the rationale for using Aspirin is that it reduces long-term cardiac risk and therefore, that's why most guidelines will put in saying that Aspirin... But there is no evidence that asymptomatic patients should be getting Clopidogrel,

because there's virtually no studies on it. And that's why the most recent guidelines have never included Clopidogrel within the best medical therapy. - [Frank] Yeah, Jonathon Beard, you had a hand up and then we're going to go to our...

- Yeah, so it's a slightly different question Frank, but if that's okay, I wanted to raise the issue of the credentialing, because my worry, we don't credential in our trials, not very much and it's very light touch, they're pragmatic trials.

The worry about credentialing in a trial is that you lose applicability for the trial, because once the trial's published, are you really going to, theoretically then, you learn you should only allow the intervention to be done by people who are credentialed,

not by everyone. - [Frank] Yeah, it's a very good point-- - So what's the point of credentialing? What is the point of credentialing? - [Frank] Sure but that's the problem with Crest, because the Crest results, as good as they were,

are probably not applicable to the whole world. And Abott, we don't want the panel to have a discussion-- - I just wanted to talk about the anti-platelets, thank you. The anti-platelet question, because you also have to consider, are you dealing with an asymptomatic patient

or just an asymptomatic artery? So if they've got symptoms in another territory, then perhaps the anti-platelet therapy's indicated. - [Frank] Okay, Sharif, You've been standing there. - [Audience Member] That's all right. The first question's for Anna,

but you're really around, just sitting among a lot of interventions, so you're very courageous... - [Anna] I call myself an interventionist as well. - Okay, so tell me, when do you do a carotid? - When do I do one? - [Audience Member] Yeah.

- [Frank] When do you recommend that one be done? - I would recommend one for a symptomatic carotid within two to three weeks of their symptoms. Females greater than 70% stenosis. Men 50-99% stenosis. - [Audience Member] So you don't recommend intervention

for 50% carotid? - Men, symptomatic, within two to three weeks, they benefited. - [Audience Member] I'll ask now, Professor Mueller... - Yeah. - So she said 50%

she'll recommend for men. What about women? - We didn't differentiate, we used a 50% threshold, because that's what's been used in the randomized trials, but we did mention that the benefit diminishes quickly. Now the simple fact is, in most of Europe now,

there is a move towards very rapid treatment. If you still have treatment up to three, four, five, six months, then yes, that would be a cause for concern in including women with a 50-69% stenosis. But I wouldn't not offer an endarterectomy to a female

who'd had multiple TIA's and who's got a 60% stenosis and were operating within seven to 14 days, I would still offer surgery to them. - Yeah but Ross, if you want to be a purist, there's no randomized trials on symptomatic patients, that shows the efficacy

of carotid endarterectomy or CAS. We all say, yes, we agree with symptomatic patients, but if you're going to be a purist, all the symptomatic landmark trials had obsolete best medical treatment. Does anybody want to join

if we have another symptomatic trial? - Well, good luck. - [Frank] Yeah, good luck, I know. - But I think what has offset that statement is the move towards very rapid treatment. I think that is the most important aspect

of managing symptomatic patients and I think that offsets the lack of optimal medical therapy in the original trials. All the changes in medical therapy. - [Frank] Richard, you want to join that? - Just the other thing to say is that,

the treatment effects were so marked in their symptomatic trials, that even if better medical therapy nudges them down a little bit, they're still going to be marked. - [Frank] Yeah, I would agree with that,

I was trying to be provocative. Ali? - John, this may be just clarification. Unless I misunderstood you, your last slide said CAS in woman was better than men. Is that correct?

- Yes, that's different from the ACAS and Crest results, as we found in our sub-group analysis when we did better with CAS. - [Audience Member] Do you have an explanation for it? - I think it's subgroup analysis and what I really want to do is a pulled analysis

with the Crest trial and look at line-item data. Frank, I have a question about the two previous topics. It's a very difficult question, Dr Beard and Dr Lau, but in these asymptomatic trials, is I've considered leading similar trials of medical therapy.

What are you going to do with those 32 sites, if they come to you with a patient, randomized symmetrical therapy, they show up with a hemisphere TIA one day ago and now their MR shows no infarct, so it's not a stroke and they're symptomatic, 90% lesion.

Are you going to recommend they continue that patient in the medical therapy arm or are you going to allow them to cross over selectively? It's a very hard question. - Well, I'm never in favor of a crossover, if I can help it.

So my answer would be, I keep them in the same arm. - [Frank] That's a philosophical question, not a medical question. And before you come back in, I'd li You said we'd have results.

The first results from Press 2 in 2000 or 2001. We want results. (laughing) Sometimes somebody should com Well look, this is what we're seeing. - I think we cannot break randomization, Frank,

for the obvious reasons and we're halfway through at this point. At this rate, we will have completed all enrollment activity by 2020. - [Frank] So you're saying not 'til 2021 will we-- - That is correct.

- [Frank] You're going to keep it secret 'til then. Gosh, that's bad. Anyhow, Richard... - I think it's really important that Crest-2 don't present results too early, because early results with a very short follow-up

will be dominated by procedural hazards and will mislead. - [Frank] Anne... - Oh, I just wanted to follow-up on the question of women and stenting, Dr. Metzmahra. But the comparison you showed us,

I think women, stenting versus endarterectomy, that was without the peri-procedural period of risk. Is that correct? - [Doctor] Yes. - So, what is the result with the peri-procedural risk? - [Doctor] It's less than that because of noise.

There's not a gender difference with the peri-procedural risk. - So did women do better or worse with stenting? - Better. - Even with the-- - But again, this is a post-hoc sub-group analysis

and we have several other trials out there. I'd like to do a pulled analysis. - [Frank] Mark, we're running out of time. Everybody wants coffee or a break. Can you sort of summarize all this...

(laughing) Clarify all the confusion? In one minute. (laughing) - In one minute. Yeah, sounds like at this point, we have absolutely no idea what to do with these patients,

in summary. (laughing) - [Frank] That's it. (applause) I think that is enough. You want to say anything else?

- No, I think we're going to get some great answers and I think BK's correct that it need to be a malleable trial, where we can always look at best medical therapy and that's always been the criticism in the past, is that this is a moving target

in terms of what is best medical therapy. So my hope is that when most of us have stopped doing carotid interventions, we'll find out what we should have been doing during our careers as surgeons. - [Frank] You come next year

and you'll find out all the answers. That's it. Coffee break. Thanks for being here. (applause)

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