Chapters Transcript Expanding Eligibility for Mechanical Thrombectomy pleasure to be here at the U. H. 2021 stroke update and nursing symposium. I'm embarrassed garage and I will be talking about the new frontiers and in the vascular thrombosis ectomy. And how do we capitalize on this effective treatment expanding the limits to probably treat more patients and and and help improving stroke outcomes and we have this effective treatment. How do we optimize the patient access to them and and delivering it fast in a fast and effective way to the largest possible population? These are my disclosures. Um So as I mentioned uh we'll go on the background of what's in the vascular from back to me the data behind the efficacy and safety of the treatment. Um How do we identify patients who may benefit and going to the future frontiers? Um Can we expand the treatment to larger strokes and more distal conclusions milder severity strokes and even in time beyond 24 hours. And for the longest time we had the mainstay of treatment being ivy Trumbull Iesus with T. P. A. And is that something that should continue with trump ectomy Or should we go directly to from victim in patients with large this conclusion and will close by what's the current status of throwback to me access. Um And how can we optimize patient access and reach fast and effective delivery of this treatment? So what's in the vascular from that? Um Well we'll use a clinical case. Um This is a patient with a left M. C. A. Acute ischemic infarction left M. C. A syndrome due to anyone inclusion as seen on the C. T. A. The patient cats can however looks very good. You do not see early ischemic changes. This is the left hemisphere looks pretty much like the right hemisphere. Looking for the symmetry on the scan. And we major. The early ischemic changes with the aspects score and the aspects score 10 is is a perfect score, meaning there are no early ischemic changes. This is the ct perfusion um images of the same patient and this is processing the images through the rabbit software. And you see here there is an area of delayed blood flow to the secluded area. As as as I said there is only one conclusion. So there is no direct flow through the M. C. A. Rather there are collateral ization of the flow. And so there is a delay more than six seconds as compared to the opposite side. And this is 150 CCs of brain tissue that at risk of em farting. And you will see me talking about something called the core infarct which is the area that's already in farted. And you will see that in in future images with a pink colored area which you don't see here. So you see zero CC. Of um farted tissue, 150 cc of tissue at risk. So this is a patient that meets the definition of a reversible neurological deficits participation with the left M. C. A syndrome stroke scale very high let's say in the upper twenties due to animal conclusion with a normal city head with the city profusion showing large tissue at risk but none in farted yet. The treatment for this is to reap refuse the occluded blood vessel. This patient indeed received I. V. T. P. A. Without improvement. So the next is to go with mechanical thrown back to me and remove the flood as fast as possible. See if the patient improved this patient was one of the patients in the select trial which is the first phase of the selected trials. And this is the first round of the angiogram showing the M. One inclusion and no flow in the M. C. A. And this is the patient after re perfusion with a stent retriever. And you see a normal flow. And then we measured that with sticky uh score initially Y zero on the final run was three. So this is a complete distortion of the blood flow. And this is the final impart on the M. R. I. You see here that there is a much smaller infarct in the sub cortical areas that is much smaller than what you have seen on the city perfusion. So this is a great imaging success that in this case translated to uh good clinical outcome. So how did we get to from back to me being one of the mainstays of acute ischemic stroke treatment. You know the reaper fusion is the mainstay of acute stroke treatment. There might be other treatments with hypothermia neural protection but this is out of this school of this toe. Um And they did. They're not proven yet but the proven treatments are re profusion. They started with Ivy TPL from aliases but the names went into trials back in the mid 19 nineties 1996 99. Yeah eight the phase two that showed that I. P. T. P. A improve patient's clinical outcomes that if you can improve the outcome and re profuse through chemical treatment from alliances with the I. V. T. P. A. And it makes sense that you can do this with mechanical from birth to me and reap refusing the blood vessel. And the and the first of his trials were the product one and Proact to and and after four Land was the main P. I. On the pro act two. And and that showed the efficacy and safety Product one was a Palestinian product one was an efficacy trial that showed that the priority client is injected to the M. C. A. Improved the outcome as compared to Hebron. But that was as compared to Hebron. Not TPM on TBS arrived. The people um abandoned this treatment. Milt is the Japanese version of the Proact trials. Um And then we had a post of getting um um data that shows the efficacy and safety of trump ectomy. People were doing the treatment um Outside of clinical trials we had clinical trials running but they took too long of a time. There were issues with the design. They did not include the right population issues with the imaging selection. And we'll talk about a lot of advancement, imaging selection and the development of the devices to get to where they could open the blood vessel in a fast way. So the first wave of trials I. M. S. Three synthesis and MR rescue did not show superiority of lumpectomy as compared to repeat again. That was in 2013 which was very bad news to the field. And then suddenly in two years in 2000 and 15 in this drug conference in Nashville Tennessee for uh randomized trials were reported chewing the efficacy and safety of thrown back to me superiority to ivy from palaces or Best medical management. Mr Clean was presented at the war stroke conference a few months before that and that was in the first six hours, 0 to 6 hours. The early window. Um as it's called at this point. And then the treatment was extended after the donor and diffused three trials up to uh 16 hours. And if you three and 24 hours you don't. So we have an efficacious and benefit treatment up to 24 hours. We'll discuss more details. So as I mentioned, the first uh wave of trials were in the early window in the first six hours. I just mentioned them. And instead of going through them but one by one will go for somebody in the Hermes meta analysis but just a quick run and this is not foreign to people. How do a major stroke outcome? You'll hear me talk a lot about the modified Rankin scale which is a seven point scale measuring the functional outcome at 90 days uh 90 day follow up and and and zero is a normal person, one with mild deficits but still no limitation of activity to more of a moderate deficits but still able to carry their daily activities on their own. Three. Just somebody as an example, most of the things are able to do but but needs assistant with walking for somebody in a wheelchair. And and five somebody was required 24 to 7 nursing care in sixes his death. And usually the good outcome in stroke trials is measured and stroke overall is measured by modified Rankin as 022. I personally believe that the three is not a bad outcome for somebody coming with a large vessel occlusion and and and large stroke. Getting them out to do most of the things that they were doing with needing some assistant with with with with walking. But again we'll talk about the outcome of this trial. So the Hermes meta analysis was a patient level meta analysis that measured. Um The that compared come back to me to best medical management including I. P. T. P. A. In the five clinical trials in the early windows. So they summed all of the data over 12 50 patients? Almost 1300 patients. And they looked at from beck to Me versus medical management. This is medical management. This is trump rectum and you see the good outcome rate is 46% from back to me in 27%. American manager. Almost 20% absolute the difference. And when you're doing an intervention you want to make sure it's safe. You're not causing more mortality and bleeds and all of that. And and this was the case. Even the very poor outcome was decreased from 2022%. Medical management 32. And and that translates and that's what I tell my patients we have a treatment um That in addition to best medical in addition to I. V. T. P. A. Would improve the outcome by 2.5 folds almost three folds. Um And and that also translated to every four patients treated one would go back to normal life. And this is very very effective treatment. Just to put this into context. You can give aspirin to 3000 patients to avoid one uh nonfatal stroke or fatal stroke. And you can give aspirin to 2000 patients. 20000.1 uh my fatal m I. Which is you know I'm not comparing giving aspirin to doing the lumpectomy but just talking about the impressive number needed to treat. Um Then you would say well how about the patients who got to be a versus not T. P. A. Actually the majority of the patients in these trials received almost 1200 patients received um T. P. A. Um and and and the and the good outcome rate and the difference between a lumpectomy and medical management. It was the same as in the overall population with with good safety profile. And when those did not get T. P. A also did not differ. And when you look at the subgroups, this is a forest plot comparing from vasectomy to medical management. So if you are on the right as a subgroup based on your age or imaging or if you receive TP or plot locations, stroke severity, time of treatment, gender where the occlusion was. And there was a tandem inclusion. If you are on the right of this line, then this favors come back to me. If you're on the left then this favors medical management including HIV TB. And you see that most of the subgroups were on the right. So that tells you that the treatment is very effective. A few subgroups crossed the line. So there was no efficacy of from back to me in those. But this to a large extent due to the design of this trial and we will discuss them more. But but that shows you that patients with good aspect small quorum far patients with Eichmann and one occlusion uh with moderate to severe strokes presenting in the first six hours from beck to me improve the clinical outcome by 2.5 to 3 times as compared to medical management. This is the standard of care of these patients should receive from back to me whether they came to a throwback to me capable center or came to a primary center in that transport the center there are groups with a large core when you have lower aspects and already established changes that you see it across the midline and there was no benefit. The more distant inclusions in the M. Two also the same and the milder strokes and those are areas that still um evolving. And uh there is evidence that hopefully will be coming soon on the different areas and we will be discussing during this presentation what's the impact of time? This is an analysis from the Hermes that looked at the likelihood of good outcome every 16 minutes from last normal three hours, four hours, five hours, six hours, seven hours, eight hours. And you see as time progressed the likelihood of good outcome decreased. So how how did you hear that time is still very important and in trump's tissue. But we'll come back with a different argument. I want you to focus on are we treating by time? Because for the longest uh period we have used time. It's three hours for TB it's 4.5 hours will be treating by tissue. Doesn't matter when the patient comes. They have a neurological deficit and we can use their images. But based on this a time trump's tissue. But keep in mind how would these trials show benefits beyond seven or eight hours when they largely included patients in the very early window 06 hours. Limited number of patients in in certain trials were up to 12 hours or beyond six hours to eight hours. And that's why they they had this these patients. But that's that's why probably you don't see uh you see the significant impact of time here but we'll talk more about that. We'll revisit um The late wonder trials don't and diffuse three. Came to look at the same question if a patient came in beyond six action. I see it in one occlusion with uh was about reversible neurological deficit. Large vessel occlusion. But yeah, not significant invited issue with this patient benefit from trumpet. We'll see. We'll see what they found. So don't use the clinical imaging mismatching which was one of the um enrollment centers. But this is again the rabbit software showing a small core. You can't even see it two CCs as compared to 100 CC of delayed flow. So there is what we call the penumbra. Large area of salvageable tissue. There was an occlusion here. It got reaper fused with the trivia stent retriever and and and it got a successful re perfusion. How did that translate to the outcomes? The good outcome rate with lumpectomy was 48% with medical management was 13. I will remind you in a little bit when we compare the early window to the late window of of of of this percentage of without. It was around 46% and now it's 48%. Pretty similar. The medical management dropped and we'll discuss that. And it was a good safety profile, mortality and very poor outcome was 25% versus 38%. Um And this translated to treating two patients uh will were will reduce disability at all the modified Rankin scales and that's amazing, 73% of the first production of dependency when you discuss with your family, a patient that needs done or diffuse three imaging profile and clinical criteria by delivering from vasectomy effectively you are reducing the likelihood of dependency by 73% production. If you use three was similar up to 16 hours while Don was up to 24 hours to his imaging selection mismatch. And you see this patient does have a 23 CCs but has a much larger area of uh delayed flow and 128 CC a. Mismatch of 105 cc 105 CC of brain tissue in the left MTs. Um And those were the ideal patients beyond six hours. Those would be the ideal patients in your practice and those were treated in diffuse three. And that resulted with outcome rate of 44% with trump ectomy 16% with medical management with a very good the safety profile. So let's revisit the time versus tissue argument. We saw in the Hermes in the first six hours. That would outcome rate with from Baltimore 46% in medical management. 27% same patients in the late window and don't defuse three 48% good outcome rate with lumpectomy and dawn, 44% good outcome rate with trump ectomy in diffuse 3 46 48 44. Pretty much the same. The patient came in in the first six hours of the patients came in beyond six hours having viable tissue, large vessel occlusion delivering successful from vegetable successful re perfusion. Uh The results were the same while you can see that medical management dropped from 27% to 13% 16% in in the late window as compared to the early window. And that's clearly because we do not give T. Pa beyond 4.5 hours. So these patients in done individually did not have GPS on board value. So like 90% of the patients, Hermes had TP maybe there is an opportunity to expand TBH beyond 4.5 hours but that shows that if the patient came in with a viable tissue regardless of time. Um That time. Uh It is not an important in not in the essence of delaying treatment but in the essence we should not stick to six hours. We can go ahead and treat the patients up to 24 hours. And that would would would conclude that actually tissue trump's time overall when we are dealing with these patients. That doesn't mean as I said that we can delay treatment. Uh This is an analysis from dawn that showed even from vasectomy benefit was reduced as time progress. The faster treatment is better almost reach medical management 24 hours. So the time is still brain. We should deliver the treatment as fast as possible. And this is how this translated to the H. A. Guidelines initially. And after the 2013 trials that did not show benefit benefit for efficacy and safety that come back to me is reasonable. It's not yet established and called for neuron demised trials that came in 2000 and 15 and showed that from veteran justification isn't safe. And this translated to being standard of care in the first six hours with the stent retrievers because the trials is 10 to 3 first. And in 2000 and 18 phone done interviews. Three it got expanded to uh 16 hours based on Donald diffuse three and 24 hours based on uh Don criteria. So this amazingly evolved within a span of five years to no benefit to significant benefit up to 24 hours. So what do we know based on this um initial few slides and what do we not know about from victim efficacy and safety. We know it is effective and safe in patients with I. C. R. And one occlusion in the first six hours based on ct or perfusion. Because some of the trials they extend I a trial used perfusion images while the other trials used aspects with a stroke scale of six or more. Um We also know that 6 to 24 hours the same patient population. I see em on inclusion uh within eyesight of six or more based on profusion images. It is identifications and safe that is thrown back to me. Uh We do not know and this is a big area of debate in the in the field if um um we should use profusion for selecting all of the patients or ct um is sufficient. Even in the late window. We do not know about patients with larger strokes large core. We do not know about digital inclusion. These are patients that were not included in the trucks. That's why we do not know. We do not know if somebody comes in with a large vessel occlusion and a lower stroke scale 0 to 5. We do not know beyond 24 hours. I just made an argument that you may be able to treat beyond uh based on tissue all only not not time. So can you use the same argument to to do it beyond 24 hours. We'll visit that and then good old T. P. A. Should we still use that prior to trump ectomy or or this is is this actually results in delays. Um So we'll we'll go through these one by one. So we'll start with the imaging selection. The ctr city profusion as I mentioned. Um C. T. U. Is the aspect score and it's an easy uh image to get fast available in every E. D. There are issues of interpretation and you have you have an expert to to to look at those. Um But this is the most advanced I'm sorry most available readily available image everywhere every indians as I said it's just the aspect score which is an 11 point score. Use the ganglia nick and Subrata. Ganguly unique areas. The more points that you lose the more imparted tissue that you have six usually to 10 is a good profile. And that's what was used in the trials that were in the early window. Well we'll see about large for and what's possible. And profusion as I mentioned used the rabbit with the four uh T. Max or delayed in blood flow um mismatch and decision has significant mismatch. So the early window trials used both the late window trials as I as I said in done in diffuse street used uh inclusion criteria. Personal the perfusion uh to have the best technological city was included but it was not the main criteria. And that's why the guidelines recommended profusion in the late window which we did in in in the in the select trial. And that's something I did what I was that we looked at the imaging selection by CT versus perfusion. And we wanted to compare city to profusion and their correlation with the clinical outcomes. We wanted to see if city can be used beyond six hours. Um um And we wanted to see how how are the different imaging profiles on cT and CT persuasion with affect our selection, affect the the the outcome. These are burning question that we have every day. Should I can I rely on the CT only or do I need uh CT perfusion to improve my my my selection. So we looked at that. This was a non randomized prospective cohort study. But in an organized fashion. Um every single patient got the same imaging profile. CTC TSC provisions with a rabbit analysis. We specified to the investigators what's a good profile and what's unfavorable or not good or poor profile. Um We left the treatment on without randomization um at the time. And this was the non randomized phase in our battle of the randomized phase we had a blinded for lab. We included patients who get from victim and medical management of patients in the first hour eight hours. I mean select to select was done before the the late winter trials come. So when dawn came we extended that to 24 hours and we included patients without baseline disability. And we included em too. And and and select two. This was nine centers trial in the in the United States. And we screened almost 5000 patients to enroll 361 patients to 85 pointed thrown back to me. And 76 went to Medical management. We asked the investigators that they selected them by profusion or CTC 60% by perfusion and and and 40% by city. But they had access to both. This was one of the things that you would have happening when you don't have a randomized trial. So what we want to look here at and I want you to think of that. Two things to hospitals. One of them you see t only to select patients. The other one is C. T. And profusion to to select patients for profusion mainly having everything else being the same. The skills of interventional ist the nursing care, the medical management which is standard. Would the two patients treated at the same two patients treated that or similar to patients treated at the two different two hospitals have similar out. This is the first question. So looking into that based on selected by cT versus selected by confusion. You have similar without come raid. And you start seeing the difference when it comes to the symptomatic hemorrhage and the mortality cT perfusion may be more specific and then uh safety and sensitive to capture those. But there was no difference overall in the outcome. Remember this was another randomized trial. That's why you can't go and say well I just don't. I have to use city profusion. Um And and people have access to both images but no difference statistically and no interaction when we looked 0 to 6 hours more than six hours. The second question that you want to look at is if the patient two patients, one of them having a good profile aspects of six or more on CT and the other one have a good profile on perfusion. If they had successful from victim, would they have similar out? Um The first one was the two different hospices here, two different patients, one of them with good profile and City, one of them with profile Ctv will they have the same response to trump? I mean they did 56% versus 57%. Uh Less of a difference when it comes to the mortality. Uh It's alright, it's alright um And then symptomatic hemorrhage. Uh But keep in mind that having a good profile on CT is not mutually exclusive of having a good profile on CTP? Actually there is an overlap between them up to 80%. But that's another argument that why do I need to use CT perfusion? There is this significant overlap. We'll see. I mean there are other elements as a symptomatic emerge. And and mortality that I mentioned that city profusion might be more sensitive and the core uh size identification But and also we looked at times six hours more than six hours. There was no difference. Um And this is looking at remember don and diffuse three used perfusion in the late window. Um So we looked at that having a good city in the late window versus a good C. T. P. In the late window. Similar good outcomes, similar mortality in the early window. I think everybody knows that from the early winter trials that used both city and sea teepee that they had similar without. If you see our outcome rates are were better than the Hermes. I mean I guess um this is the evolution of people gaining experience with trump Etame and improving overall. Um We published this paper in annals of neurology a little over a year now. Which in which we concluded that um what I mentioned that there is a high overlap between CT and CT perfusion patients who were treated based on CT had similar outcomes to those treated based on city profusion patients with good imaging or favorable profile on CT and favorable global city profusion had similar response to throw it back to me, as I mentioned in terms of symptomatic hemorrhage and mortality. Profusion has an edge in identifying these patients based on the core size ah and other elements I will mention. But you know how does that reflect to our practices and this is probably more philosophical but you will see that it's it's reality. I want you to think of these scenarios. You have a patient with a large vessel occlusion and you have the first hospital that is highly selected only treat patients per the guidelines per protocol. I'm not encouraging people to treat out guidelines. But just talking about the letter of the low versus the soul of the practice. I only treat young patients. I only treat patients with perfect imaging. I end up out of 100 patients excluding 17 uh patients treating 30. Um and actually, you know, my outcomes are great, 60% of my patients end up having functional independence. But I ended up only benefiting 18 patients while a more liberal approach in hospital b treating more inclusive treating patients maybe with more extreme exchanges, maybe older patients. So they end up treating more patients. That could outcome rate is less. It's 40%. But 28 great patients end up benefiting treatment versus 18 patients. I mean, I mean think in my mind, I know which hospital I want to go to. But this is how we take the guidelines. We take the evidence and we start applying with our practices and what was not covered yet. And and and and how we put our protocol also. Um um and and and and at one point you get to this denominator fallacy. You know, I look so good because I treat only the perfect patients. But what you want treated to do is to benefit more patients as much as possible. Okay, well now we talked about the perfect patients. We talked about what was included in the clinical trials, but not every patient present to the emergency room is a perfect patient. What we may see is larger strokes, more distal conclusions, milder strokes will go over those and the evidence available. So these are the perfect patients that were included in the France. I showed you the Perfect city, Perfect city Profusion, small core or no core and and and no extreme exchanges. But sometimes the picture is different. This is a patient with a very large for almost 100 CC with a high power density. We talked about symmetry and symmetry in chile and look at the difference between the two. Um and um you see an aspect of four here. I mean what do we do with these patients? Those patients were excluded from the clinical trials that showed efficacy and safety of from back to me and you come to the risk benefit ratio which we do with every single patients in the emergency room. How do we how do we treat these? These patients? Should I um intervene or or not? If if if if I do well there's already large stroke. They are less likely to benefit. If I open the blood vessel on and part of the issue there is risk completing. But if I don't they will continue to in fart they will have a very large stroke, they will hermit they will die. Um So maybe from vasectomy can help me avoiding this very poor outcome. Well maybe it can do more but we don't we don't know yet. So we looked at that in the select the trial. It was pre specified. Other than the initial paper that I showed you and analysts neurology. This was published in jama neurology and looked at the large poor population specifically out of selected population. We had 105 patients with large ports on C. T. Or C. T. P. That received from victims or medical management. Not in a randomized fashion. We're randomizing and select two but selector was based on select. So let's see what we found in select. So those 105 patients 62 received from victim before he received medical management. So no question selection bias is probably existed there. The younger patients. Healthier patients received from ketamine and the other one's receive medical magnet. Of course we adjusted for that. But if you look the good outcome rate with one victim was around 30 31% with medical management was 13%. You're not talking anymore about those about forties fifties and sixties percent good outcome that you showed that I showed you the small core. In fact you're talking about 30 and 13 but this is still better than medical management. Uh And and and this was with a good safety profile mortality was reduced from 42% to 29%. This translated to statistical significance. Whether you looked at the M. R. S. 0 to 2. The functional independence or the shift. See there is a shift to better outcome across the modified brian kings. The treatment was safe. The mortality reduced. There were more hemorrhages. This is a large core. But we talked about the risk completed opening the blood vessel in a large part of tissue. But this was not statistically significant. And the final infarct volume that developed the evolution from the initial and part to the whole oven fart was almost cut in half with from back to me and the party growth almost cut in half. So this reduced the herniation and the hemicrania as I mentioned before. Um And this is how we built select two. Based on select. We said I said this was not randomized in select. So we went and randomized and then select which is currently on going. We took patients with um a large vessel occlusion in the I. C. N. N. One up to 24 hours. No baseline disabilities drug scale of six or more. But those are that were not included in the Hermes. And don't interviews three. Those are with lower aspects 3 to 5 and a four infarct of uh 50 cc or more random being randomized Currently from victory versus medical management. 30 centers across the world and New Age is one of the centers. These are our centers in select. Do we have a center up in Canada. About um two thirds of the centers in the United States. We have five centers in spain and and and four and um Australia and new Zealand. All of our centers have been very effective and we just crossed the 200 patients enrollment which is the a pre specified interim analysis or pretty anxious at this at this point. Our data during board is is looking at that. Well we'll see if this has any early signal or we should continue to enroll more patients. These are our end rolling um centers. This is what I was at U. T. And usually no surprise volume center and this is where the global P. I. Is. But all of our centers are contributing and contributing very well actually since we prepared this, we have three more enrollments and um we are up and running in uhh and and we enrolled the patient Dr Sunder rajan and doctor who are the P. I. Is here and we have another center in Cleveland and Cleveland clinic. And these are our enrollments, we almost enrolled 50 patients internationally, which is very good and very important for the trial generalized ability. Um and you see that all of our centers and falling actually every single center in the trial has enrolled a patient which is very good success for the organization of trial and the selection of the sides. We'll see what what will happen. As I said, we are going through an interim analysis. Maybe we'll go to the next in terminal 3 80. The total enrollment goal is five sixties 23 more years. This maybe as early as a few months. We'll see. We'll see what happens about clutch location. Well, we talked about patients come in with I. C. N. N. One but sometimes they come with more distal occlusion. And when you look at them, you usually it's milder deficits and usually um it's um um a smaller area at risk. You see the difference between the two. So the risk benefit ratio that I talked about earlier is different here. Should I intervene or not? Can I benefit the patient? Is there more risk of intervening? Going back to the guidelines with the reasonable. I mean reasonable is not standard of care, reasonable. Some people are more aggressive than others. Some practices are more conservative than others. Some interventional iStar. Um more prone to do some procedures than others time of the day. Is the patient here on a Wednesday afternoon versus uh a saturday night. Uh Those are all affected the treatment because we don't have randomized. That's where I'm too much trials are important and and the argument is valid. You know, this is a smaller caliber blood vessels. Men are more trip to us uh than the M. One segment or the I. C. A. So the risk of deception, bleeding um And and it's smaller tissue address so that there's lower likelihood of benefits. So we published on that a few years ago this was retrospective. Ah And we looked at we have the largest actually cohort more than 500 patients from victory versus medical management. And the good outcome rate was 63 with from Bethany versus 36 with medical man. So with a good safety profile. So this is a signal for potential benefit. I do not know if there will be a randomized trial with mm two. S. Or not. But these are good signals for for for treating these patients will see how the evidence. How about a patient who comes in with mild deficit M. One I see occlusion. But the patient stroke scale is three or four. Sometimes people do not even get A. C. T. A. Uh for these patients and can't blame them. But even if they did. And if there is this conclusion going back to the risk benefit ratio. So I said look at the vision, say they're doing pretty good. Um You know I mean why should I intervene? Um But if you don't you have a large vessel occlusion the patient may deteriorate may lose their collaterals. Um And they would do much worse than an I. H. Of 0 to 5. And at the same time you come back and say but their stroke scale is it too? If I intervene? If I have a dissection, if I have bleeding from the intervention I will make them towards all of those are valid. Um We also um you know looked at that and this is a retrospective cohort study from um six centers in the United States and spain and we looked at Trombetta me versus medical management structure overall we did not find difference. Medical management actually was 57% from latin was 64% and there was higher complication rate with trump at 22% versus 1% with medical management. But the devil is in the details. This is how you improve your selection. This is how you get to identify which patients should I treat or not. So these are we separated those into those who had distal occlusion um and M. M. 23 and four and uh a C a conclusion. And you see that medical management did much better than from victim 80% vs 70% with a better safety profile versus the proximal occlusion. The I. C. N. N. One convinced him it'd better 60% versus 45%. Still higher complication rates. And this is where where is the sweet spot? How do I identify my patients? And there may be an area for you know, profusion imaging. Looking at the collaterals different things too. To better identify the patients will see, see how things evolve in the future. But those are the initials signals, there are two ongoing trials. One is called Window Hello, which is a United States trial and one is called an extremist. Mhm. Which is a european trial. We'll see the results from that. This applies to all prices. Can we go beyond 24 or should we stop to 24 hours? This is an analysis that we looked at from the diffused free trial and we looked at patients who after 24 hours had persistent penumbra, tissue address versus those who did not have persistent penumbra. This patient, you see after 24 hours there is still a lot of agreeing a lot of tissue address. This patient you don't have tissue address. This is persistent penumbra. This is no persistent penumbra. Um um um the ones who do not have persistent penumbra as in this patient um did not have an extension of the empire. This is the the the image. Um at 24 hours. Around 44 CCs. With the difference in in in the calculations, uh the cuts, it's our etcetera. It was the same impart at 150 hours. This is the patients who have persistent banana brah. You see at 24 hours, they have about 27 CCs of comfort at uh six days. They have 70 species of the park. So this makes a an argument that if a patient missed the 24 came in with a banana barrel profile. Probably uh from back to me or any other re perfusion measure would be um something to consider. Again there is no round in my child. I do not know if there will ever be around to my trial for more than power. But but this is for practice consideration. Maybe there will be more data that we uh do not um you know make this hard line uh and and protocol and say well only within 24 hours patients may present unknown last time. Well they have a viable tissue. They are worth consideration from Netanyahu say. And this is this is the outcome from this study that was published in in in stroke that uh those who did not have persistent penumbra had with medical management. This is not with Tom benton had 39% without con versus those who persistently numbers continue to fart and had much worse outcome and neurological worsening and only 9% good outcome. So this is opportunity for us to probably treat more patients and then the last few the last couple of targets will be on TPN LGBT access. Um So T. P. A. And and this this this really sounds weird. Um T. P. A. Was the standard of care and and and it's still um um but it was the only mainstay of treatment and the question was well I'm giving T. P. A. Should I or should I not ad from back to me to TP and we saw that the initial phase showed no benefit And the devices improve the selection improved the treatment improved and and trump. Ectomy is clearly adjunctive treatment that can improve the outcome and even superior to TP. And when they were compared to the head. But now the question is should I even give T. P. A. Or I am delaying the patient treatment? I am taking the patient to the wrong center and I'm not making an argument for either. But when people start thinking within peace lines and executed clinical trials to go directly to from vasectomy versus a standard model of giving TPS and go into from vitamin and see how much the pendulum uh moved within within a few years. So so far we have five front demise trials on this already. Um And and those trials mainly asked well is from vector mean alone, direct from vector me non inferior to throw the victim a blast T. P. A. Or abridging therapy. And and two trials actually demonstrated that it's not inferior. So you can argue I should go to the restroom alone. That that's the direct empty and the D. V. T. Chinese and japanese trial. And there are three trials that looked at that and actually failed to show non inferiority of direct from victory versus from victims from alliances, meaning that going directly from victim E is not non inferior. That that doesn't mean it's inferior but it's not non inferior to give in T. P. A. So that argue that we should continue with the current model and give TP. And that's the skip trials have directed mr clean no ivy confusing results. Um and I think this is how you, you know, identify what do you do in your system and how can you adapt into that? Definitely there are patients would benefit from direct from victim and there are patients that don't but we do not have evidence at this point to stop giving TP and and and and and and bypassing it. Can we post for a second? I'm not sure what happened. So those trials as I mentioned did not give us its factory answer. Um and there were issues with the design. I mean the direct empty that's kept the DVT trial included only patients presenting to the throne victims. You presented the lumpectomy center whether you pass by bass TP or not how much gain of time you get and and and in those patients who are not getting Tps really really is TBH being completed before from victims starts. If if if if most of the patients TB is not completed, how do you expect it to to work the non inferiority margin that they choose their worldwide and arbitrary the enrollment. The number of patients wasn't large to show differences. I mentioned in one of the trials, 87% of the patients. Almost all of the patients who got T. P. A. Did not get the T. P. A completed before going from back to me and those were chinese and japanese trials. Um and those three here that did not use the full dose of T. P. A. In china. You have to pay for your T. P. A. So the patients um there were selection biases and who could pay and who could not pay. Uh in terms of including them in the and the and the trial. So we also within select looked at this question uh in an article that we published in in neurology earlier this year whether we should do direct from vasectomy or bridging therapy. And and actually um we found benefit of the bridging therapy with giving ivy tpf 7% without conferences. 44%. This was statistically significant for the M. R. 0 to 2 or to the shift as well. But again, selection selection selection which patient would benefit which patients may not benefit. Within our sample, we looked at those with stroke scale of less than 15 versus more than 15 or more. And you see with less than 15 from valises plus trump ectomy did better than from vasectomy alone versus more than 15. There was no difference between the two. So maybe patients with more severe stroke patients who are where tP is less likely to work and we know that the larger the more severe stroke it was likely that there's benefits. Even patients with very severe strokes were excluded initially from the guidelines. Um these are patients are less likely to benefit so maybe this is an opportunity to triage patients in a certain way and and and and identify those who should go directly to from vitamin. Then we looked at the stroke size and those patients with smaller cores less than 50 CCs benefit from the bridging therapy versus the larger cores did not benefit from bridging therapy. And there is a good argument here to make because a lot of the patients may not get TP if they have very large pores. So we covered a lot of these unknowns and we showed potential evidence from select two for imaging selection by C. T. And C. T. P. We uh show potential evidence in uh and in patients with large uh fours and we'll see what selector will show. I mean there is an area with the distal occlusion. There is no randomized trial yet ongoing. There is a trial in europe for middle vessel occlusion. We'll see what that shows mild strokes that are two ongoing trials. As I mentioned, we'll see that. And can we treat beyond 24 hours? I'm not sure there will ever be trial because those patients with largest abortion usually present early on. You're not going to have the population to exclude trial. And then the debate about the T. P. A so far we should not by bass teapot. But how can we shape our access models and our triage systems to efficiently do that or um certain patients take them where they can receive from back to me we looked into thrown back to me access and this is a project that received an american Heart Association american stroke Association award where we mapped the access um in the United States of all the United States population forced from victory access and as we know earlier treatment better outcomes the current model. Um and that we have right now is to take to the closest hospital that deliver from valises and then to transfer to from back to me but we know that transfer times are prolonged. This is something that we all should work on improving within the within our system. The faster that you give the patient the treatment is is better. Um But what did we find? What is the current access? We looked at the data based on the I. C. B. 10 codes and stratified patients based on the centers those who received um from back to me the centers who delivered at least one from back to me were considered from victim the center and those who did not deliver any from back to me during a those years were considered none from victims centers. We used the 2010 population will update it when we have the 2000 and 20 populations and we did advanced geo mapping and and calculated driving distances from the the center of the population to the closest thrown back to me center. So at the time there were 1941 stroke treating centers. And by the way just on the methodology of this there is no resource like you think you will go to the H. A. Website and I will find what are the crumble. Is the center's only where the from victims the centers and map those and all of that. That is not the case that is not available unfortunately. So we had to do all of this um method a logical approach with I. C. D. 10 codes and its etcetera. So 1941 centers who would treat stroke the majority as you may imagine were none from victims the centers uh and only 713 were from victims centers. The good news because when this paper was under a review the reviewer asked us to uh since we have the 2015 data and 2017 data to look at what changed and actually we found that delivering from back to me the number of centers increased from 5 77 to 700 13 centers 24%. I mean those are not comprehensive stroke centers as I said at least once from victim e. Was enough to consider us from Victory center but that shows you that you know the treatment is being more available initially here at U. H. We have it in one center now we have it to who knows what the future would carry but that's owing to the advanced evidence from the guidelines and the randomized trials. So so that's that's these are good news. So let's look at the current access how many americans have access to directly uh to to to from back to me. So we said you have direct access if you work within 15 minutes from from back to me center. And and and and we looked at 30 minutes and 60 minutes you can find all of those in the paper. We mapped all the United States and you see there are large areas that you don't see much in there because there is not much population in there. But only 20% of americans had direct access within 15 the prospect of 61 million is based on the 2010 census. If you look within 30 minutes this went to 31% of the americans. Um if you go directly to the front, back to the center of 95 million increase in 10%. So how how do you optimize it? We looked at two models. The first one is the flipping model using greedy algorithm. You you look at the population that if you flip one center from being none from vector meter from vector me center you will benefit the most number of patients being having direct access and of course easy said than done because you have to have the resources, the interventional list and just read the training etcetera. But but let's see this. Your closest center is non from victims center will come and make it a uh from victim the center that was the first optimization of the village of the second one was bypassing. Well if you're non from victims center and you're within 15 minutes of a from victims center extra drive, you would be by bass going directly to the to the front victims center. Let's see what the two models did. We said that the current access was 20% within 15 minutes, flipping 10% improved the access by 7.5% flipping 20% of the centers uh increased by additional 5%. You see so the more that you flip you will get less bang for your buck um and and this number of patients benefiting bypassing for 15 minutes, increased the access by 16.7%. Almost almost doubled it by passing by 30 minutes only had additional benefits of 6%. You see once you start bypassing more than 15 minutes, you you are actually not as effective and almost same as as flipping. So you know that the ideal model is probably somewhere in between and its center specific ah and and system specific you have to give access to the most number of patients and deliver the treatment as fast effective. Well. Well, you know, if you're not bypassing and if you if this, you know there's a lot of training and methodological stuff and logistics involved in that. And E. M. S. It's alright so this is a big question in the field but how can you can you improve your time's going to from victim if you're transferring the patient? So this is a paper that we published um three or four months ago in Jama neurology where we took almost 2500 patients from centers in the United States and um spain. And and we looked at the patients who got transferred from primary center from victim the center Comprehensive center and um um those who got stopped in the E. D. And got their bit of their images versus those who went directly to the throne, vasectomy took to the front to the engine's sweet. How how did the time clear? How did the outcomes fare? Uh So the the idea here is you get a stroke you get transferred to the closest uh stroke central. It's let's say um one of our system centers and then you get your initial images you get T. P. A. And then you get transferred to the comprehensive stroke center. Hopefully hopefully we can achieve that transfer within within 60 minutes. Which is is a good target. If you again stop and do another image and and spend another 30 minutes to go to the engine. Sweet. And this is an additional 30 minutes. We want not to do that. We want to bypass that if possible. In certain patients with neurological examination change of if they get transferred efficiently within 60 minutes, maybe we can improve our outcomes. Maybe we can go directly to the interest and reap refuse the patient faster. So in our analysis. Mm hmm. Um these are from last known world to arrival. So those are not the numbers matter in, in, in in in blue but the ones in orange are the ones that matter beat imaging delayed arrival to from victims center to the procedure. From doing directly going. Getting um first growing puncture 34 minutes to 60 minutes. An additional 24 minutes within the first six hours, 23 minutes beyond the six hours. It was also 24 minutes. And this was the same. You're in coal during weekends, during weekdays, After hours. During hours. The same pattern of the late 25 to 30 minutes. About the outcome's going directly to the NGO resulted in 53% good outcome versus the repeat imaging. 37%. Of course. There are some more details into that. There might be sicker patients with repeat images. That's why you repeated their imaging. All of this is understood but you control what you can control. You have the perfect patients coming in within excellent imaging at the initial center. Probably going directly to the ngos Sweden. This. This needs war too. Coming to fruition would improve the outcome and actually reduce the mortality. That's why I say because some people would say well if I go directly to the angel, I don't know what's going on. Maybe the patient's blood etcetera etcetera. This was actually a saver. Um and improve the out and this was the same within the 0 to 6 hours, more than six hours. I fully understand. There is randomized data from dawn and diffuse three and you should do profusion and these centers may not have profusion but this is showing you that we may evolve to an extent that even in the late window and there are there was one randomized trial, the angio cath that was done in spain that should go in directly to the engine for the outcome safe. There is another multi center randomized child because engine that was in one center. Um that's looking at the same question. So this is looking into the future and and some of the things they make that may happen. Well one may say well I can only do this during work hours when everybody here versus uncle hours. People are not here. I can't go to residential. Please keep in mind that early notification occurs when a patient comes into one of the hospital center. As we get to notify, we get cold for them from the transfer center. So we can have the NGO team ready if we know that there is a large vessel occlusion. And and and you see during regular hours the good outcome rage was better during the on call ours. The good outcome Rage was better, same safety profile and the time to the NGO also was faster because of the pre notification and having the team available. So with all of that there is no one size fits all. There is no magic. Um stick that you wind and you get everything face. So how do we optimize the next, how do we improve the patient's access and optimize that the treatment outcomes since it's an effective treatments? Well I mean there are things at higher levels and legislations and um maybe planning things in advance and having the capable centers within certain populations. You know there are heat maps where strokes are more likely to happen. Higher populations. It's our sorrow within certain distances more hospitals with trump. That's great training neurologists, radiologists, neurosurgeons to do the procedure and being able to deliver the treatments. Um try adding in the field one of the solutions maybe this is this is something we I mentioned in in in in our T. P. A paper that stroke skills less than 15 versus more than 15. And I understand there are issues with can can E. M. S do a good stroke scale it starts tomorrow but this is one of the resolutions. I I you know I have to point out the all of the data. So there was a trial in spain and Catalonia that looked at identifying the view on the field and taking them to the front victim hospital versus the original triage model and there was actually no difference in the outcomes but there is more data on how distant how much faster you drive, how how how how more you drive to take the patient to the front and center. And I showed you things access that once you drive beyond 15 minutes actually you don't get much more benefit that are the mobile stroke unit came from Houston were jim Karada around the mobile stroke unit clinical trial that was published recently in your condition should improve the outcome and this is a cartoon that dr four line actually but in 1986 but this is history. His his thought of having an M. R. I. On the mobile stroke unit. Um very innovative more than 30 years ago looking at a potential solution and this is uh this required to my one of my mentors in Houston with the mobile stroke unit bypassing the navy T hospital and again no one size fits all. I showed you a model where you can go to the primary center transferred to the trump ectomy center and going directly to the engine and you can give your T. P. A faster and may have as good of outcomes that so that depends on how you can optimize your system and there is the trip and treat not the drip and ship this this position in India is going on a motorcycle with his uh come to do aspiration on a patient in the hospital where there is no throwback to me this model is being done in the Mount Sinai system in new york the the interventional and and this is something that is being done here at Ahuja. Um so there are different models that you can adapt but um faster transfer protocols getting the patients within 60 minutes optimize the imaging protocols. Where does their patients get there image? We really built for this island. The group here did a really nice job getting the C. T. A. And the outside facility identifying the L. V. O. Um and and letting the engine team you know so we can capitalize on that if we have good transfer time. If certain patient go directly to the engine maybe we can have an efficient system you know for the for the fun of it until all of these things being done. Maybe you would consider moving to a closer to a throwback to me hospital or no where's your intervention analyst and where their whereabouts and you know build a wall around them from victim in hospital. So all patients put from the hospital. So let's let's go back and summarize this. Um and the journey of from Dmitri we started I'm not going to start at the far left where I started where there was no evidence. We started with several randomized trials showing benefit in the first six hours and two showing benefits of 24 hours. We have selected to another large court trials. That looking at the large course select two is looking at the imaging selection if we do ct perfusion, if there is additional benefits of that. So this is something that should be coming a bit next few years, mild strokes that are clinical trials. So you might have an LBO stroke scale of 0 to 5 that you would consider treating uh tiene que I mean this was out of this group of this uh hope but this is something to consider. There is timeless that's looking at and other trials that looking at giving from polis is up to 24 um hours. So there's more opportunity to um treat patients and overall team K. Versus T. P. A. S. Is the different types of subjects and the efficacy of that. And this is one of the things that we are evolving as a system into maybe giving neural protection at the primary hospital and transferring the patients. And the charm trial is looking at that and and maybe looking at posture this regulation. And we're going to do more in the in the select trials with the Director NGO with more distal occlusion and we'll see what the what the future carries. Thank you so much for your attention Created by
