TEVAR vs Standard Medical Therapy in Uncomplicated Type B Aortic Dissection: A Roundtable with the IMPROVE-AD, EARNEST and SUNDAY Trial Investigators

For the SWS sportscast, I'm Safen. Today's episode tackles one of the most debated questions in contemporary awards excertly. What do we actually do with an uncomplicated IPA audit dissection? The easiest things to treat is compelling and these patients have just experience a catastrophic event, they are all they storm, the false luminous open and pressurized, and we know that over the following months and years, a significant proportion will develop an arrestment of degeneration, progression, or rupture. And yet, the word uncomplicated is doing a lot of the heavy lifting. These patients by definition have no evidence of end-walking ischemia or aortic rupture, and immediate risk is lower and tevar, while far less invasive and open surgery is not without procedure, has a reachable weight-typed, high-sections, spinal cord ischemia, and the larger among knowns of a stand graft left in the dissected aorta are rate concerns. This is precisely the clinical tension that three major endomides control trials are now trying to resolve concurrently and with complementary design, and enough mythological difference to make today's conversation genuinely important. I'm delighted to be joined today by three vascular surgeons who are not simply observers of this debate, they are leading it. Professor Ferras Mousse is a professor of vascular surgery at Baylor College of Medicine, and the principal investigator of the improved radiating trial, the largest of all three, involving 1,100 patients across 16 North American centers. Professor Colin Bechner is a professor of vascular surgery at Imperial College London and Leesie Ernest's trial, the UK based study with a particular focus on cost effectiveness and patient reported outcomes, and Professor Jacob Bartsel is a consultant vascular surgeon and always then more, and one of the principal investigators of the Sunday trial, a skinny navy and let's study targets in the subcute phase specifically, with access to some of the worst most complete national registry for work. Professor Mousse, Professor Bechner, professor Bartsel, welcome and thank you for joining us. Thank you very much. Thank you. Good to be here. Thanks. Before we get into the individual trials, I'd like to briefly step back and ask a question that I suspect many of our listeners have wondered. We have had a set, we have had a talk, we have had an aesthetic style, we have metaanalysis suggesting benefits from teeth war and metaanalysis suggesting no difference. We have guidelines from both side of the Atlantic and broadly recommend a selective approach to teeth war and uncomplicated disease without really defining what selective means in practice. Professor Mousse, you helped establish the feasibility of one in a randomized trial and uncomplicated type biotic dissection at a time many of the feeds out that it was achievable. Looking back at those early feasibility surveys, what was the strongest argument against the trial and how did you answer it? Right. So the strongest argument was that actually, it's like any any other trial. It's hard to convince a surgeon and hard to convince a patient to enroll. That is not to dissimilar from any other cardiovascular study. Mind you that this is not like hard disease where the disease very prevalent. Aortic section is not that common even in a large country like the US. So the main limitation was really the the number required to treat and the feasibility of enrolling those patients. Vasiabek, no. Ernest was designed in part because the UK vascular surgery community felt existing evidence was insufficient to regard practice. When you look at the instant data, no survival benefit at two years, but a clear benefit immersion only after five years and instead except what does that tell us about how we have been designed in and borrowing trials and this disease and what gap does Ernest specifically set out to fill? So you're right. The UK vascular surgery community was not convinced by these trials and felt the further evidence was necessary. These trials that are not really different from many other situations when you have randomized controlled trials. The set up and running of a randomized controlled trial is faintly difficult to fund, it's faintly difficult to convince people to be with you and to join with you in the trials and it's constrained by money, time, everyone wants an answer now and doesn't want to wait five or ten years for the answer and the number of patients of course is also really important. So there are a lot of issues with these trials because of these general circumstances. But if you run trials that are inadequately powered or don't take into their account the longer term in this cohort of young fit, often fit people which is so important, you can end up making the wrong decisions about treatment of patients. So I think that was all important. I think that as well as the small numbers, as well as the fact that there may well have been biases in terms of that, it was also in a small number of centres which were expert centres. It wasn't specifically for the UK, it wasn't in a publicly funded health system and it wasn't in an area where every centre that did Tiva joined in. And so we really had a need to run a trial such as Ernest. The binary classification that has government management for decades was built on what happens in the first two weeks. It says very little about what the aorta will do over the next five or ten years. The absence of acute complications that presentation is not the same as long-term benignity and the feeling so in a sense to refine the category through high risk anatomical features have not yet produced a consensus strong enough to change guidelines. First of all, does the label uncomplicated to serve us or is it time to replace it with something more granular? Yeah, it's a good question. I think uncomplicated still does serve a purpose, but I think we need to be clear about what that means. I mean what it means to serve a purpose. It describes, I mean it describes your patient's condition today. I mean there's no rupture, there's no malperfusion. Nothing to tell you that there's an intervention required. But that's not the same as telling us what that aorta will do over the next five or ten years or so. But at the same time, I mean I think we do need greater granularity, but I would be cautious and I think if you're asking Colin what degree that we'd be cautious about replacing one binary label with another one such as high risk uncomplicated. Because the difference, I think people forget that between a prognostic factor and a predictive factor. So a lot of these high risk features, they might be prognostic, that might mean that they might have an adverse outcome at some point, but that's not the same thing is that they benefit more from a tabar. I mean that requires evidence which we really don't have. So I think we could still use the term uncomplicated, but obviously still do a trial and all the like the Sunday earnest and improve. I mean they'll move us from these descriptive risk mark or classification that actually guides treatment instead of just using these as a prognostic classification. That's an excellent point. I'd like to spend more some more time now on the methodological choices in each trial, because I think the differences between them are not just academic, they reflect genuinely different hypotheses about what matter most in this disease. Professor Nusa, improve XZ is the largest of three 1100 patients, 60 centers, six year for what window and a composite primary end point of all course death and measure aortic complications. The composite is broad, aortic wrap charm of the fuse in which a great dissection spinal cord is chemia, stroke and aortic invention. Some might argue that such a wide net with diluting the signal or capturing events that are clinically very different from another. How do you defend that design choice and what does improve a uniquely author, there's more that more targeted trial can know. Yeah, that's excellent question. It honestly comes down to basics of trial. You pick a high event rate and a reasonable effect size, so the pick mortality. So if you want to show that Tivar improves mortality, any treatment that you're going to pick cannot have an effect size that is huge. Let's say Tivar cannot reduce mortality by 80%, not even 70%, not even 50%, at best, at best would be 30%. So to power for 30% risk reduction with a high power over 80% power, this would require over 2000 patients. So that becomes not feasible. So the arts of trial design is you've got to pick something that happens frequent, matters to patients and also will allow you to design within reason. limits. That's what happened and instead they overestimated the effect size of T var they ended up with an underpowered study. That's the premise of picking an endpoint. Now the ones that we picked, you're right, it is a white thing. It is, it kind of filters out the noise of all death. Death could happen, a patient could have a car accident and die in the, in any trial and that will be considered death. It is not aortic related death. It's death or cancer or you know if they live enough they die of different disease. So then you could think of it as lots of noise in a big thing like death. However, when you couple death with few things that don't, don't happen frequently like malperfusion stroke and all that could happen after intervention. But the other thing that happens and people talk about is like, oh, back in the day they used to get an open, big repair people used to fear that a lot and that matter to patients or we consider that to be a part of the endpoint. You can I just say open repair is bad. You can say if you have an complex endovascular repair like a, you know, for vessel, fenisrate and branched. Then that also puts a patient at a risk of paraplegia and this is not readily available everywhere and expertise matter. So then becomes an important to patient, important from cost effectiveness, standpoint, and same thing with the repeat T var. I got to have to say we do not consider patients who get medical therapy and then go on to get a T var as an intervention. That is part of standard of care. We consider those who get a big repair, whether open and end of to be an endpoint. So in a nutshell, you got to have to be reasonable when you design and within the confines of what statistically appropriate for the funding agency in the U.S. that is. That's really interesting. Thank you. Professor Batsili, some days primary endpoint is all cause mortality at five years. We must trade forward for three. Your trial is even driven, powered on 80 deaths using Scandinavian National Registry to achieve new complete flow. That is genuinely an elegant design. But I'd like to push you on it. All cause mortality simplifies its education and avoids composite dilution. But does it risk missing what T var may actually achieve? Because T var's most plausible benefit may be in preventing aortic degeneration, not in reducing early deaths. Yeah, that's an excellent question and fear us in calling. I have discussed this quite a bit. And I think it's a legitimate concern, but actually that's exactly why we chose all cause mortality. We chose it not because it's the easiest endpoint because it's actually the hardest endpoint to misinterpret at the end of the day. And it's unambiguous, kind of as you've said, it's resistant to adjudication, independent of any local thresholds for re-intervention. And I think that really matters in any of these intervention trials because it's difficult. Some centers might re-intervene at different thresholds or whatnot and that can be really difficult to delineate. I mean, if this trial it shows that, yeah, that early T var, for example, improves CT scans, but doesn't really improve how long or how well a patient lives. You would have to ask yourself, is that really clinically important? But I get it. I mean, mortality isn't the whole story. I mean, we include the important secondary events, re-interventions, complications, quality of life and costs and whatnot. But in a way, and you have to be clear that our trials have been driven because we don't expect an early mortality effect. We hypothesize that the benefit is actually long-term. And I think if T var shows that there's an improved survival, our secondary outcomes would obviously add further information, and particularly if T var shows there's no survival information, it benefit. Then I think that the secondary outcomes will go far to show that, you know, any of these other secondary or mentions other things I mentioned, that there's a difference there. But that decision was deliberate for some of the reasons you just mentioned. It's really great to see it from your point of view. Now, Professor Picnod, Ernest Safe say different approach. A composite of a articulated mortality, CV permanent neurological deficit and CV permanent cardiorespiratory failure, more specific, and with a plan into an analysis assessment procedural safety and aortic remodeling at one year. You've also built health economic analysis into the primary point. And Professor Picnod, I'll leave it to our listeners to decide whether that reflects the unique rig of the Ernest team or simply the realities of working with the NHS. Why was cost effectiveness a priori? And do you think that kind of data will actually shift clinical decision-making? So we went for a composite primary endpoint because our patients wanted it after talking to all of our patients. We designed a number of secondary endpoints. One of those is cost effectiveness. We chose to analyse cost effectiveness because it really is the responsible thing to do in a publicly funded healthcare system with limited finances. And I think as physicians, we do have a responsibility to provide cost effective healthcare. There are those that are involved in the institutions such as Nice, as you know, from the under-ism discussions that we had a few years ago that it's irresponsible to fund a highly expensive, ineffective treatment or a treatment that only provides minimal improvements in quality adjusted life years over something that's cheap and will provide many more quality adjusted life years for the population. And so when there is limited finances, you have to do something along those lines. So I think it's responsible. I think it's the right thing to do and I think it will provide really interesting information for us all. But your question on whether it will actually shift clinical decision-making is a very wise level-headed question and I can think of lots of examples where cardiovascular surgeons, cardiologists and every other specialty has continued to use non-cost effective treatments. It's okay to do that as long as there is, it's a new technology which is developing that there might be other perceived advantages but we will have to argue our case to the National Institute of Clinical Excellence, I suspect if it doesn't come out particularly within those costing boundaries. That's a very compelling point of view. But before we go deep into methodology, I think I'll listen to deserve status reports. These trials, they're not hypothetical, they're like, they're in real impatience right now. And the cardiovascular surgery community is auction closed. First of us later, Sunday was among the first of the three trials to open. What can you share with our listeners today? How is recruitment progressing? Yeah, actually, you know, today we just had our 200th patient recruited. I haven't called but it was actually a new no DS in Malmö recruited patient number 200. So that was great news. And I should add, I mentioned this in the last question that it's event driven. So you know, our sample size estimates approximately 550 patients that could be more or less, it's all driven by the number of events. And fortunately, we have a good group. And when we do this for each other, we present sort of all three trials collectively. I just like to add one of the thought because I think it was a loaded question you gave to Colin. You know, all these factors that go in to make the right decision. One thing I think it's important overarching this question of what it is we'll show. I think we need to remember that even showing equivalency is still a valuable result. I don't think a trial has to prove that there's a difference. I think the knowledge we obtain in our clinical practice when we talk with the patients say, look, there's no real difference whether we go this way or this way with a strategy that's still really valuable in a conversation with the patient as far as I'm concerned. Professor Becnault, Ernest enrolled his first patient in March 2025. What have the first months of recruitment looked like in practice? Are the eligibility quite sure you're working as intended when they meet real patients every clinics and has anything surprised you yet? We have had issues with the research infrastructure that that is set up obviously around the UK. The lead time into setting up centers has been really long in some in some centers. So we struggle with all of that. More interestingly, we've seen lots and lots of screaming logs from patients who have reported many unsuitable patients and many complex patients or many complicated patients. And we've discussed the reasons why we've seen so many complicated cases at length. I think that what surprised me, what shouldn't have surprised me, but probably did surprise me a little bit, is that we all ended up looking for that perfect dissection case that comes in, has his blood pressure treatment for three days, then gets better, then goes to the ward and then gets randomised, and then we do the stent, either in the same hospital sitting at three months. But it doesn't really exist. Every single dissection is different in terms of its pathology and anatomy, and it's the symptoms that it's sort of induces. And so we have done quite a lot of work in trying to come to a consensus, or at least a more rounded definition of uncomplicated. We've done some work looking at trying to increase the numbers of different patterns of dissection that could go into the trial without straining outside of the losing criteria. And we've been very clear in asking centres to randomise everyone that they possibly can around the UK. And with our different ways of looking at this trial, the numbers will start to increase. But I think we're right at the bottom of our acceptable level at this 18 months period, and we need to improve. The idea is the most ambitious in scale. How is recruitment tracking, and has coordinating the trial of the size of course such a heterogeneous healthcare landscape flowing any expected operational challenges? Right, so thank you. The US is a different healthcare system, obviously, than both the UK and Europe. In general, it's fee for service. So if you do a procedure, you get paid for it. If you don't do a procedure, you don't get paid for it. Not only you as a surgeon, but you and the hospital mind you that if you do a procedure in a hospital that's not equipped, and you have a complication, then that beats, you know, the idea that do T-VAR in every hospital in the country. But the healthcare system is such that you try to do as many as possible with the capacity that you have. So that's the infrastructure that we currently have. Plus what I just mentioned is the fee for service. So our challenge is really to convince faster surgeons to give up the revenue from doing a procedure in order to support science. And that is not intuitive in the US. It's not something that's done. It's, and also it's not unique for faster surgery. But faster surgeons have different minds in that cardiologist where some one reason or the other, they do enroll thousands upon thousands of patients with medical therapy versus PCI for MI patients. But they don't seem to, Vascular Surgeons don't seem to do the same for this trial. Now we are at 223, I think, today we enrolled one, so 224. And again, in the US, not everybody believes in the need for the trial because I think, you know, the economic consequences of that is that you lose revenue. And that's really what we're up against. Last really enlightening about conditions, across the Atlantic, thank you. One of the most important questions and uncomplicated diabetes section management is not just whether to treat, it's who to treat. And each of your trials had made distinct choices about inclusion and exclusion criteria. First of all, illness has taken the interest instead of including patients with uncomplicated diabetes section during pregnancy, a subgroup explicitly excluded from many aortic trials. Can you explain the rationale here? And more broadly, illness, dyslustrations requiring corrected or innominate territorial vasculization to create a landing zone. Of those with plant-visual artery intervention, how does that affect the genera's ability of your findings to re-work practice? We're not, let's just be clear, advocating stenting during pregnancy. But if you have a tight biaortic dissection when you're a pregnant and then or during birth, and then you are still within that first three months, why are you any different to anyone else that has a tight biaortic dissection over the long term? You still got a full slume on which is profused, you're still at risk of dilatation. And what we don't know is where the T-VAR will induce thrombosis, full slume and remodeling in a lady who had a dissection during pregnancy just as anyone else because of high potential or high potential or lathoroscratic disease. So I think it's reasonable. I don't think it'll be a huge number. We wanted to be as inclusive as possible, which is why we really left it in. As for the carotid and the enominant and the visceral vessels, well we brought our surgeons together in a big group and we were very clear, or they were very clear with me, I should say, that they wanted a trial where we were tackling standard type biaortic dissection requiring standard T-VAR and they thought that if we were going to be re-bascarizing the carotid arteries or the enominant artery or going into the arch, that there was a greater risk of having significant longer complications and that this would be not the trial that they wanted to run. So when we get to the end of our trial, when we get to the end of our trial, we will have results on this group of patients and we will not be able to answer whether or not non-a non-b patients should be treated with T-VAR, but we will have a sort of definite answer for that standard T-VAR for type biaortic dissection at home. These stratifies patients based on high risk anatomical features, aortic diameter of 40 millimeter or more, primary and tree tear of 10 millimeter or more, or a four-slummed diameter of 22 millimeter or more. Do you believe those markers that I will be identified who will progress? And is there a risk that by including all cameras and reliant on subgroup analysis, you may need to wait several more years before specific patient phenotype emerges from your data? So we do include all cameras. This stratification is done after enrolling the patient, patient sign a consent, then myself, let's say a side PI and the coordinator sit in front of the computer, look on the images and fill in the what we call the imaging CRFs, okay, and decide and pick if the patient has one of these features that you mentioned and we store those. At the end, we will have those patients who have, let's say, pick an aortic diameter of 40 versus those without and by stratifying we're including we're making sure the two buckets are equal risk. I don't want somebody come back at the end and say, well, you just stented everybody that has a diameter of 20 millimeter. Of course, they're going to do fine. As opposed to, oh, you didn't, you treated medically all those who have a diameter of 45 millimeter. Of course, they're going to need an open, third, abdominal repair and so on. So by stratifying, we try to risk stratification to make sure the two arms are of equal risk. Now, if you ask me about my opinion about the high risk features, I think they as Jacob mentioned, they ought to be studied prospectively. I think this debate is more heated in the US. If I come up with something tomorrow, tear sizes 12 millimeter, not 10 millimeter, it won't by the end of the day make it into the guidelines. I mean, that's how the US function. As opposed to by in Europe, in Europe, thankfully, there are people who actually scrutinize the data and so on. So the value of those is yet to be determined. But in the trial, we just try to make sure the two arms are equal. So people in the US do not criticize it as completely whacked in favor of one verse, the other. Professor Wesley, sounds like solutions with established connective tissue disorders and pre-existing for abdominal aneurysms. Some argue this creates a healthier cohort whose resource may not apply to the most complex cases on our lists. How do you defend that boundary? That's a good question. I mean, we're open to that limitation. I guess you would have to distinguish between generalizability, which we've mentioned a few times and then biological coherence. And I suppose when you get into biological coherence, that's also a question, because I mean, even when we're talking about the exclusions of patients that have pathology that goes up in the arch, in fact, they're going to excluded the U.K. because I guess some people might feel that's a bit of a different disease process there. And I think that's really getting into limitations of our understanding of what's going on with the dissected aorta. Having settled out, though, we kind of acknowledge, though, that connective tissue disease patients and patients with pre-existing thoracal abdominal aneurysms. that is sort of the natural treatment of these patients isn't a question of covering a primary entry. It's a different process from that point on. So I guess I'd kind of challenge that we're choosing a healthier cohort. We're just trying to do a best, and we try to do as much, I mean, we're pretty literal on our inclusion and exclusion criteria, but we did want to maintain some form of biological and coherent cohort, and I think both Colin and Ferris were into better, but that's just where we sort of said, okay, we're going to set boundaries here with these patients, because I think many of us agree that they are a sort of a different patient. I think their treatment trajectory, as I just mentioned, is a bit different, and that was a decision there was quite deliberate. I think that's very intriguing, and I might deserve a whole episode and it's so. I'd like to explore the intervention in more detail, because T.Va is not a single standard diaspora procedure. Professor Musa, improve A.D. promise operators to select any FDA-approved San Quartz, with flexibility over adjunctive techniques, including additional San Quartz, typewriter standing and other endovascular maneuvers. You've mirrored, reared, heterogeneity, intentionally, but does that heterogeneity compromise your ability to attribute outcomes to T.Va itself? And how will you account for the fact that operator experience and institution of volume were very enormously across 60 centers? Right. Very good question, very common question that we're not evaluating T.Va as a procedure. So you can do the T.Va upside down, backwards, flick it over, put it in your pocket, and then clean it up, spit on it, put it back into the patient. It's not really the question that we're trying to answer. We're trying to answer a strategy of treatment, of upfront treatment, with a stent, versus delayed treatment, with a stent if needed, okay? So that stent could be one piece, could be a piece, and another piece to the silia, could be two pieces plus a bear stent, or a brand stent, as in the U.S. as I just mentioned to you, the more we put stent in, the more we get paid. Professor Blutsley, Sunday permits advanced junk safety techniques, including pericode and stabilised, all the clinicians this question. Ernesto interestingly does not recommend stabilised, though it doesn't explicitly exclude it. Professor Beckman. Could you explain that decision for Ernesto and Professor Blutsley? When you look at the immersion data on stabilised, which piece to improve forced human trombosis and biotically modelling significantly, do you think future trials will need to treat it as a separate intervention arm, rather than an object? When we came to write the trial, we had to define what was mandatory, what was recommended, and what was excluded in our interventions, it has to be very clear about our intervention. And we ended up with very few things that we agreed should be mandatory. Come into the conclusion, this is mainly a pragmatic trial, which is kind of what Ferris is saying. This is a trial of a strategy versus not, but of course we said you need to put the tea bar in and close the primary entry tear. You need to use extra guided imaging. You need to do a completion angiogram. We need a CT after the procedure within the first six weeks. So very little guidance there, but we decided that we would give recommendations, which would be that you could choose the length of the stand, although we would expect you to land in a straight path of the air, or to avoid entry tears, we would expect sizing to be 10% or less for a deception, we would avoid ballooning if not all these sorts of things. And within that group of things that we shouldn't do, we discussed a joint of techniques. Now we were never going to, a joint of techniques and different other things. We were never going to be so restrictive that we cut off certain different procedures and parts. So we said that we're not recommending stabilise, but if you want to use stabilise or petticoats, especially if you need to, then that's fine, we'll allow it in. In actual fact, there are very few people that are doing stabilise within the UK and I don't think we're going to have great enough numbers to perform any subgroup analysis and SRE, join with others to have a look at the results of it. And so that's how it came about. I think, you know, that really gets at the whole circularity of the discussion. And I have great respect for people doing randomized control trials and we've met with people with experience in doing randomized control trials. And they said, as you can see with these three trials, that they necessarily have to be pragmatic. It's a strategy because people are doing different things and fear us hit the nail on the head. We can't dictate, we can't put out a protocol, it says, you have to do it this way, is this not going to happen? You know, I'm really interested in the stabilised technique. We don't do it, it's not very common in the Nordic countries. But we're talking to people who do stabilise, I guess using the word zealot is a bit of an exaggeration. But they're really convinced that you get the full remodeling. And I think everyone's aware, though, that comes at a cost and we have some patients who've been pretty well close to stabilise, I mean, they get really, you know, a lot of coverage of the order, extensive treatment of the iliacs and stuff like that. And they're risky procedures and we've had some adverse events. And you have to remember that, you have to bear that in mind that, okay, you believe that improving remodeling improves or survival, then you're exposing these patients to some big risks. And so, for those people who believe that stabilise is the way to go, then they should be also part of this trial. But having said that, I kind of agree with Colin, I don't know if we have enough patients to do any really valuable subgrouping out, but I think it's important at the end there because there are some sites in the sunny trial that believe in stabilise and they want to do that. So, I think that should be allowed. I would add an important thing, I mean, we talked about Tabar and, you know, the general of the ability and then different types of procedures are done out there. The stain could be said for the medical arm and the same could be said about the circularity about the medical treatment because we had a lot of input from site saying we should have a standard procedure for the medical treatment and we said, we'll hold on. There is no evidence for which medicine is best. So why would we standardise what should be done? That's why we do the trials to find out, is there one medical treatment that's better than other? Is there one procedure in Tabar that's better than other? That's why we do the trial instead of doing it the other way around, standardise and then randomise patients. It's just putting the horse before the carriage. For those who's going to listen to this conversation and duty to pedicote or stabilise for uncomplicated tuddies, we're meaning no rupture, no malperfusion, let's just be clear. And even the company that makes that stain, this is an invitation from these three trials. Invitation to study this in patient and collect like a hundred because guess what? There is no randomise or even a well-documented cohort of patient who received a bear stand that had been studied properly and followed for many years in this patient population. And in a comparative study, not in a single arm. So that's really an invitation of the ask the company that makes a bear stand. They were not interested, and therefore their sales I think in Europe is pretty dismal. In the US I think it's also saying the same thing is very selective sites that do it routinely and some others never will consider it. But that's one way of doing it is team up with us, the three of us. Now to the elephant, there are disagreements on timing and please correct me if I'm wrong. I think the trials have gone through some changes. And for VG, opens its enrollment window at 48 hours after symptoms onset, meaning you are prepared to randomise patients who are still in the acute phase. Sunday says wait, no enrollment before one week. And the focus on the subcute window up to 90 days, earnest opens at 10 days. First of all, Lily, can you explain the reasoning behind that specific choice? Yeah, sure. And that actually that topic or issue was the most discussed. in our protocol, involvement, evolution. I think originally we, I can't remember where we started, but we were down to seven days and then five days and then people said what to it. 'Cause we do see some patients who are quite stable and doing well and you think okay, they're ready to go home. But then suddenly it dawned us. We're like, well, wait a second. If we just move it down to one day or two day, then it's a different trial. 'Cause we're kind of constrained by the good argument as the distinction between a acute and a subacute dissection. So if you start including patients at day zero, then basically you're going to the adsorb trial. You're saying, let's just treat any dissection that comes in the door. Whereas, I mean, if you go back to the thinking of the trial, it's okay, they become stable. Again, all these terms are so debatable, it's uncomplicated, is there valuable, is there value in a prophylactic treatment for these patients? What's the timeline? Well, again, we started seven days and if you look at some of the literature, there's a Swedish study said of patients who come in that are well doing well and stable and uncomplicated, the majority of those that convert to some type of complicated acquisition, that's within one week. And I would say, I can't remember the specifics, but I would imagine them, I'm pretty certain that the majority of those were within the first 48 hours. So we're very wary of them going too early because if you include them, and then they, for example, from the medical arm and they convert to complications, I think they'll just skew our results. So we wanted to get away from the acute period somewhat. And seven days was also rather practical or pragmatic. Majorities patients are admitted usually seven to 10 days or something like that, so that worked well for most of the departments. So that's a good question. - Thank you. Professor Moussa, improve AD with enrolled patients as early as 48 hours. Professor Batsley is just so good. It was a bit too soon. What do you think about that? - Ed Zorb showed that you can stand people, stand them within three days, three to five days. So we know it's safe, but we know it could be risky if done in all patients. You approach the patient within 48 hours to enroll. We do not recommend, and most sites actually do not necessarily do not really do. So we picked the 48 hours so we can approach them in the hospital. And they don't leave the hospital before we approach them and randomize it because once they leave the hospital, it becomes much harder to enroll a patient. We approach them in 48 hours. We randomize them within a week. That gives them a time between the two days and a week to kind of declare if they're going to have a complication. Some of them, like in the literature, is around 10% that thing happened. Developing a profusion or rupture or severe pain that is not letting up. So those patients is just a matter of logistical flow in the US because once they leave in the US, it's not like in Europe where they're kind of registered through their zip code and this and that. Here in the US, you can get treated in Texas and then leave and go to Louisiana and get a T-Var, go to New York and fly in California. So that kind of thing happens to capture those patients. - Thank you. Professor Vicknell, where does Ernest actually stand on this time and debate? - Originally, when we were planning the trial, we had a lot of debate just as Jacob did. We decided that if you, if you stented right at the beginning, you were stenting or not stenting. All those uncomplicated patients that became complicated and it was a slightly different trial. We wanted a very clean group of patients who had proven themselves to be uncomplicated and then we're talking about long term differences in complications and need for major aortic surgery. So I was with Jacob very much so. What actually happened halfway throughout our starting to recruit is that a lot of centers said to us, it's really impractical 10 days because what happens is that our patients go home at five, six, seven days. And we end up having to bring them back and then you're given the patient information sheet and then they go home and they have to come back again and it, it, people got cold feet, lost interest in trying to recruit someone. And so we actually have moved to five days based on the fact that most patients will have had their complications by five days, 48 hours, 72 hours almost certainly. There's only a few that are going to become complicated after that. And it's a really practical thing for us to do. So I've been swayed by both Jacob and Fira's. - Now one of the most consistent finding zone favourable of Tiva from a tour ball from instead, et cetera, and for multiple observational trials and series is superior aortic remodeling, force human transverses with action in force human diameter and stabilization of the aorta. - First of all, is that a cervix end point we should trust? Or is it possible that a radiographic abuser does not reliably translate into outcomes that matter to patients, survival, freedom, family intervention and quality of life? - No, and that would be the hope. I think that's the rationale. That's why people say they should be tempted because you look at the remodeling, you think it's favourable. But that's obviously where both the adsorbed and instead trial demonstrated the better remodeling, but no difference in survival. And I think it's interesting, a lot of the retrospective studies I've looked at, like I read data, for example, that there's no difference in re-interventions. So you have the medical, you have patients treated medically and you have patients through the Tava. The patients get a Tava, they're not done. They come back and actually numerically, there was no statistical difference, but they get re-intervened upon more often than that medical arm. - So it's not like you go in, fix something, and you say, okay, now you're healthy, no need for anything more, and you'll live longer. That's just not the case. And that actually, in essence, is why we're doing a trial. And I would add to it, that's why we touched on it a bit before, but I'm very wary of composite outcomes. I see the value and I see how, I mean, the allure is that you get more endpoints. So you're done with your trial faster, but the hypothetical there is that look at your outcomes, one arm will have a bunch of re-interventions, you know, sort of similar quality of life, and similar mortality. But because there are more interventions in one arm, you say, okay, this is a better treatment. I think the matter is, and it's not the only thing, but it is survival. And then you take your secondary outcomes, it's like, what about these factors? 'Cause my fear would be to say, yeah, composite outcome difference, okay, any difference in survival, the study wasn't powered for that. We can't answer that, what about this? Well, we can't answer that. So you just have a composite outcome, which sometimes is good, but I don't think it's that often the case. Now I want to turn to the best medical therapy because it's the comparator arm and all the three of your trials. And I think sometimes it gets taken for granted. The recent analysis by Martin and Kaleis, which incidentally includes Professor Bickman as a good author, highlighted that anti-hypertensive medication adherence and chronic type belted bisection is poor. Only 43% of patients were highly adherent, and up to 21 were poorly compliant. Now, if BMT is not being delivered, as I'm telling it, the comparator arm is systematically weaker than the protocol assumes. Professor Bickman, how is earnest residents? - I wanted to go as far as testing urine to make sure that they were taking the tablet, so an enhanced medical therapy. But in actual fact, that probably isn't the right thing to do, we needed to test standard of care now versus one intervention. And so we are taking a pragmatic approach to it. We are trying to firstly understand how best medical therapy is delivered, because it's not always delivered by Vascular Surgeons and Dissection Clinics in the UK. It's very terrible. We are trying to produce guideline-based recommendations for GP's general practitioner's specialist and patients. We are trying to increase the understanding of type Aortic Dissection, which incidentally in that paper I'll adherence, a lot the knowledge about people's condition that people had would really poor, and probably related to whether or not they took the blood pressure tablets. So knowledge and from patients. And so we are doing our best to encourage people to follow the right path with best medical therapy, but we have to accept that there are some people that won't take it presumably. because it makes them feel awful. And if it makes them feel awful and they don't take it, maybe Tiva is the right thing to do if it improves their quality of life. First of all, it's Lily. Some days, registry linkage means your dare may ultimately extend to 10 years. If the five year primary endpoint is neutral, but later mortality diverges beyond that, as in said the exact suggested it might, how does the feeds handle a result that keeps evolving? And at what point do we just call it? Yeah, I wish it could be that black and white and say, okay, we call it at this point, but that's kind of the beauty and advantage of doing a trial. You could see, you know, they gave our one trial's call and mention, you know, we followed that avidly, you know, per years, you just, there's still value actually maybe even more value as you go farther out. And it sort of brings me back to the point about my concern about composite outcomes, because Comps outcomes did, you've done faster, you can get results out at like two or three years, but the long term results, I think, are the ones that are really interesting. Yeah, those are the ones that really were the nuances that help you in your discussions with patients. I, you know, like, like the small aneurysm trial, for example, that outcome was death. And if you look at, you know, a lot of the patients who were just under surveillance, they ultimately did go undergo treatment for their aneurysm. I think there's 75%. That's not a failure. You know, people, I'd say all was 75% of the patients crossed over. It's not. You can still say to your patient, look, there's no benefit for us to treat you early and proactively. We can wait. And yes, you may get treated later. That's still super valuable information. So I think long-term data is as valuable if not more. Yeah, I think that's very interesting. Right now, today, each of your teams is sitting in front of patients with a fresh dissection, asking them to consent to a trial where we generally do not know which arm is better. That is the honest truth of thickly voice. And it is also for many patients, a deeply unsettling thing to hear. They have just to write a catastrophic aortic event. They want you to tell them what to do. Professor Bickmer, how do you have that conversation? How do you communicate genuine uncertainty to someone in that position? It's not me that doesn't know. It's the whole world that doesn't know. And I like to say that we've got this child up and running. And the reason we've got it up and running successfully is because there is real clinical echo poise in terms of what we should be doing. I think in general, patients have been really, really receptive to listening about the child and to working it through with us. We have got some, you know, the usual clinical patient information sheets and videos and decision aids which help the patients through deciding. I was really worried when I started that this was asking patients to do quite something quite significant to have the rest extent put inside them for this trial and that we will get a really high refusal rate, but we haven't. And I guess I'm just very proud of all of our research staff and nurses and all the consultants around the country. They must be giving the right message that we really need to know the answer to this question. Professor Moussaib, Professor Bickner, Professor Bock's Lily, thank you. Three trials, any question that has resisted to clean and serve for longer than any of us would have liked. Perhaps in a few years, you will not have solved it entirely, but we will have earned the right to stop guessing. In a serious weather temptation to act is always present, these trials represent something important. A commitment to find it not first. Thank you for listening to the SVS broadcast. We will include key references and links to the trial protocols and the episode notes. We hope to welcome you back when the first results begin to emerge. (upbeat music)