Chapters Transcript Video Trial Highlights from TCT 2024 Dr. Deepak Talreja, Dr. Luke Kohan, and Dr. Matthew Summers share key data from several cardiology trials presented at TCT 2024. Welcome everyone to grand rounds. Uh November of 2024. This is defect to region. On behalf of myself, I Cohen and Matt Summers. We're excited to bring you a, a slightly different kind of grand rounds. Today, we all just recently attended the Trans Cap Therapeutics conference along with uh with uh just under a dozen of our colleagues in Washington DC from October 27th to October 30th. The first comment I would make is thank you to the entire division. We're looking at the um work together to go to different conferences around it. Those of us get to attend. It's always because there's folks on back uh back here and hopefully we balance it out over the course of the year. So we all help each other get to conferences. And what I'm hoping we can do more and more is bring back some of what we learned at those conferences. So we've got three exciting combined talks. So I'll move pretty quickly through mine. We each picked a couple trials or topics of interest from TCT and thought they would be a broad general interest. Um Again, like in, in the structural division for example, Matt and I went and Dave Adler and Park Perik and Josh Cohen were kind enough to man the service. And for each division, it's been like that, whether it's TCT or any other conference, um Clint camp at, attended his first TCT this time around. And uh we had a lot of fun out there together. You see the main stage, you see us all uh enjoying some time together as well as learning uh having a chance to meet with industry colleagues, meet with each other and uh bring something back. These are some of the the dinners we had all together. So there was certainly some fun and then we had some uh some need to be on some of the main stages. Matt gave an incredible talk. I think he's going to reprise some of here on an A I system to predict structural heart interventions. That was the dossi system we'll hear about. I had the opportunity to do some training on valve deployments and coronary access afterwards. So as I looked at the trials, I picked two trials to go through and I'm going to move at a pretty brisk pace. There's certainly a lot of online data. You can go dig into deeper or talk to me later if you want to hear more. But the reason I chose these two trials is we participated in both of them. Eclipse was a large scale randomized trial of orbital atherectomy versus conventional balloon. Angioplasty in severely calcified coronary arteries prior to implantation of a drug leading stent. It's really the first of its kind of trial J curtain was the person who presented it on the stage. And what we really discussed was that coronary lesion calcification is associated with greater PCI complexity. It's associated with stent under expansion and an increased rate of early and late adverse events. Our team is so good. We take these lesions on regularly but a real question has been in the spectrum of having more and more tools to deal with coronary. Calcium would ablating or fracturing that calcium improving the compliance of the lesion. Would it potentially facilitate stent delivery and help with long term outcomes? And we looked at one specific atherectomy device that we have access to which is an orbital atherectomy platform. And so in this trial, this was a large scale randomized trial which we participated in comparing orbital arthrectomy to plain old conventional balloon angioplasty. Prior to drug loing stent implantation, there were about 150 us sites involved about 2000 patients. Some of the key entry criteria are shown there had to be calcium by either fluoroscopy or by imaging ibis or OCT. There was a separate oct cohort and the patients were randomized after a wire crossed the lesion in 1 to 1 fashion to either orbital atherectomy as a lesion preparation strategy, starting with a 1.25 millimeter classic crown and then balloon predilation or alternatively, they were randomized to a conventional angioplasty strategy where they could have balloons per operator discretion, including for example, cutting balloons and so forth. And then they received second generation DSS with attention to one year target vessel failure. And there was also a 500 patient substudy looking at oct performance. Um the study interventions, the orbital atherectomy arm received balloon predilatation, then orbital atherectomy and ultimately had to have mandatory balloon dilatation after atherectomy prior to des implantation. And the sizing of balloons was was uh pre specified conventional balloon, angioplasty arm received the standard uh litany of drug of balloon catheters. We have including cutting and scoring balloons and then a drug alluding stent to follow in this trial. One thing that was really important is crossovers were strongly discouraged and they'll always happen because patients come first. But it was, it was hoped that there would be little crossover and this trial really achieved that based on characteristics are standard for the patients. We see this is probably one of the higher levels of CKD and dialysis dependent patients that we've seen in interventional trials. In the past. The EF on average was 55 there was a significant incidence of PV D prior PC and about 10% had prior cabbage lesion treatments were similar between the two intravascular imaging, either OCT or IVIS was performed in 66. 0% of patients. That's a, that's a nice number to see it's pretty high for, you know, traditional trials of angioplasty we've looked at in general, the time to intervention was a little bit longer in the oral arthrectomy arm. And the number of catheters used was a little bit higher in that group. But the trial achieved the intent of very little crossover, 2% in the oral arthrectomy arm and just under 5% in the balloon angioplasty arm. So certainly there were patients who had to cross over and that makes sense. These are heavily calcified lesions and occasionally equipment simply can't be delivered until more lesion modification is performed at the end of the day. Procedural success was obtained in a very impressive 98 plus percent of patients in both groups. Final timy three flow was virtually 99% in both groups. And we see procedural success and strategy success was overall very high and there were no differences between the two groups. So it shows again that the group involved was talented at what they did and got nice results in these patients. Procedural complications were also very rare, slow, slow flow was the only thing that was a little bit more common in the orbital arthrectomy arm, which is not unexpected because we are potentially shaving off some of that plaque. But the rest of the findings were really balanced well between the two groups including perforation, which was very rare spasm thrombus. All these were very low incidence events, which is again, very reassuring for both technologies in our hands. In the oct cohort, we saw something interesting, which is when you use OCT to measure the exact lumen size. The orbital arthrectomy group did have a slightly greater uh immediate gain in that in that minimal stent area where the maximum calcium occurred. The blue angioplasty group had a median size of 7.05 and the Orbi Arthor directy group said 0.44 while those crossed each other and it was not, did not meet statistical significance. You see that trend to better lesion prep potentially allowing greater maximal gain. But it is interesting, it's a very small differential and did not meet statistical significance, which I think is important. And when we looked at target vessel failure at one year, there was no statistically significant difference between the two arms. Some note that the orbit arthrectomy has a slightly higher but non statistically significantly different level. Most of that is really in the immediate term, if you look the two curves are entirely parallel as you follow them out to one year. So this was ultimately a negative trial. There was not a significant decrease in target vessel failure at one year in the group that received oral arthrectomy compared to balloon angioplasty. But there's some really interesting thing about this trial and this quote negative trial that are worth looking at also looking at 30 day outcomes. The death rate was extremely low in both groups it was a tiny bit higher. The all cause and cardiac death in the in the group treated with orbital arthrectomy. But a lot of that was not deviated related and was later. And that number of zero in the balloon angioplasty arm is lower than most traditional trials. So how much of this is the play of chance is difficult to say. But outcomes were good in both groups and if you look at one year outcomes that was 30 days, at one year, outcomes were virtually identical. So no, no real harm or benefit in this group, just better stent delivery in some of the patients. The couple of things that are really interesting, this is one target vessel failure stratified by the enrollment cohort showed that if you forget to skip which therapy they got. But look at those that got OCT and those that didn't get OCT. And what you see is the group that did have OCT performed had markedly better outcomes over the long run, regardless of which strategy they were treated. And our chip team has very much been on the bandwagon of getting us all to think about whether it's ibis or OCT, taking a better look at our vessels as we fix them. And this again adds to that robust data stream. Although this wasn't the intent of the trial, it really does show the benefit of very careful vessel analysis, post stent implantation to make sure we're maximally expanded. I know, some of our newer colleagues are interested in OCT. And hopefully, that's something we'll hear more about in the future. And we obviously have ibis available to us readily right now. The other thing that I would point out before I talk about study limitations is this was an interesting trial. This is now the era of trials that had to live through the COVID era. And so one of the real difficulties in this trial was because of COVID enrollment was very slow. It was at a time period that was challenging for trial enrollment and for operator use. And so the the trial was spread out in a longer longitudinal fashion than is typical. And I'll show this again in the next trial I show, but that probably had some implications for operator comfort patients. The number of patients not enrolled due to extremely calcified lesions was significant. Remember in this trial, every patient we looked at to enroll and I know from enrolling a couple of these, we had to have equipoise as to whether we could just use a balloon. So one important thing that we leave this trial with is this, this looks at the patient that could either have balloon, angioplasty or could have orbital arthrectomy. Those patients who have so much calcium that the operator at the beginning said I really need to do some sort of debulking strategy. We're not included in the in this trial. And that's important. I don't want us to take home the message that orbit arthrectomy doesn't really add much to balloon angioplasty because that's in patients that we have equipoise for where the results were fairly similar in those patients. We think up front, we need to do some sort of debulking. They were not included in this trial. And that's addressed by previous data which has shown great success with our different techniques for addressing calcium in the coronary vessels. And again, because of COVID, once again, this trial spanned a six year period, which is pretty long for a 2000 patient trial in such a common disease space. During that time period, there were significant changes in treatment practices. New calcium modifying devices were introduced and the use of intravascular ultrasound grew significantly. And so that really complicates some of the analysis in this trial and in all the trials during this time period, and it's something to think about nothing anyone would have anticipated. So this these results really apply only to lesion preparation with oral arthrectomy compared to balloon angioplasty using non compliant scoring and cutting balloons in patients who are felt to be appropriate. Candidates for either operators and patients were not blinded, differences could also be a result of some other treatments. So my conclusions are in this trial, we saw that the routine use of orbital arthrectomy did not improve your your stent expansion or reduce target vessel failure at one year compared with conventional balloon angioplasty for preparation of severely coronary, calcified coronary lesions prior to stent implantation. When we look at patients that could receive either therapy, based on the operator's judgment, extremely calcified lesions that the operator believed would be balloon uncross or undilated were not included in the randomization. And so that's a group that really, we still have to think about lesion prep very aggressively in and again, uh this was a good trial in that there was a low crossover but there still was crossover. And so one lesson is we have to be prepared even in those patients that we thought could receive either therapy for the potential for a need for crossover and most lesions were qualified based on angiography. This is an older, it started an older period. But overall use of intravascular imaging was high. It would be interesting to repeat this trial and look at those patients by Ibis or that were identified to have a higher or circumferential calcium burden. Again, probably many of those patients would be excluded because many of us would maybe more aggressively consider calcium treatment ahead of time with one of the calcium debulking therapies. So last take home messages, adequate stent expansion and low rates of adverse outcomes are achievable with conventional balloon angioplasty in a substantial portion of severely calcified lesions. If we pay meticulous attention to lesion preparation, increased use of imaging, which has been the trend for the last decade. Once again, is substantiated by this trial. And it's great to see the the panoply of tools available to us to take care of these patients. And randomized control trials are essential to inform treatment strategies in this space. And we are continue to be involved in more and more trials. We have upcoming Ibis trials and trials with, with Ella devices and so forth. And so always try to help think about powering these trials. Our center has a tremendous volume we take care of and great experience amongst our clinicians. So kudos to our research team, for all the work they do to help us make this possible. And for all clinicians, let's let's work together to keep informed on what trials are happening around us and keep enrolling patients. All right, my second trial, we'll move through even a little more quickly. This is a structural heart trial that again we participated in. And so I thought it would be nice to show the outcomes of this trial here. These are the one year outcomes of the accurate neo two platform. It's a transcatheter aortic valve that's been used in all risk patients with severe A S. This is the accurate ID E trial. A couple of things quickly. This system is actually in use commercially across the world. There are 60 countries outside the US. It does not yet have us approval, but with 80,000 plus patients treated with this platform globally. And if you look at the major trials that have informed and allowed approve approval across the world. These trials have been impressive. The rates of stroke re hospitalization pacemaker are very low and consistent with previous trials across devices. We've been involved in all cause mortality less than 1% at 30 days and less than 5% at one year. In this trial including high risk patients, stroke rate was less than 1% and that 30 day period, um A V gradient was in the single digits even at one year and PV L greater than or equal to moderate was low throughout. So this this this device has performed well in global analysis. This is now the US based trial. The tor world has become complex as we have many different devices around it. We've had previous ground rounds addressing some of these, this is this device. It has a self expanding very open frame with those three large times now because it has less metal we pre dilate in every case beforehand. So patients get a bav either prior to or or really most often the day of valve implantation 100% of the time in this valve. It has porcine pericardial leaflets which are in a super annular position, inner and outer ceiling skirts and an upper crown to anchor on the super annular side. Just part of the design. Originally, um sizes varied from 23 to 27 and predilation was required in this trial trial design was a 1 to 1 randomization of the accurate neo two valve, about 750 patients to a mixed control of the valves that were available at that time and standard of care, those were the chronic evolut valve, a self expanding valve again. And the SAPIEN valve by Edwards, which is a balloon expandable valve. We use both of these valves and because the trial again ran for a relatively longer time period, we used several generations. The latest generation in each case of both of these platforms, the primary input was all cause mortality and stroke or rehospitalization at one year. Key inclusion criteria were what we use for any TAVR evaluation. The patient had to have a reduced aortic valve area less than one centimeter squared or a low indexed valve area for patients outside of the standard body size. And one of the three, either a mean gradient greater than 40 or a max velocity of greater than 4.0 or a Doppler velocity index of less than 0.25 along with symptoms of heart failure. And a heart team had to ultimately evaluate each patient. So one of the top two criteria and then symptoms and a heart team evaluation, which has been the standard of care. And we'll hear more about some of that later. I'm not going to read through the exclusion criteria. They were standard for TVER trials, but this lists some of them out patients couldn't have a lot of A I other significant valve disease and ef less than 20 or recent clinical events, they had to be stabilized. This was a non inferiority analysis for accurate neo two versus those two traditionally used valves in their 3rd and 4th generations. And the non inferiority margin of 8% was pre specified, which would be about a one third reduction from the expected rate. These statistics are complicated at the end of the day. The thing I would point out which I've alluded to in the last trial is this is a long running trial, 1500 subjects across 70 centers from the US and Canada, amongst which we participated as well. And because COVID hit in two waves across this, you saw initially starting from June 19th, June of 2019 through February of 2020 enrollment was ramping up nicely. Then COVID hit and we basically had a, a absolute, almost shut down in enrollment for a period of a year. Then we had some recovery and then subsequent waves of COVID again, restrained enrollment in this trial that makes the trial challenging because again, the comparator arms continue to evolve during this now four year period, the trials, the trial is ongoing. And so we're comparing against a multitude of different valves. And secondly, 11 real limitation of this trial is that the average site had three months between implants. And what that means is operator experience was limited most sites 60% of sites did less than 10 cases. Only 7% of sites did 25 or more cases. So this is also an examination of when there's limited implanting done by a team or operators. You know, the lack of familiarity, potentially that might become a factor in that. We're fortunate to have a large volume center and we did well in this trial. But that really is one thing that in retrospect appeared to impact this trial significantly. This is a big slide. I'm not going to read it all. Baseline characteristics. Average age was 78. 25% of patients were in the higher extreme risk group. 40% were in an immediate risk group and another 40% approx were in a low risk group. They had a medical history and pre procedure evaluation. Very consistent with past trials, procedural characteristics, successful deployment of the valve was seen more than 98% of the time. Again, alluding to the skill of the operators, the teams and the ease of use even in a valve that patients that the operators are using less frequently. And there was a very low complication rate. When you look across the group, 99% of patients in the accurate trial had predilatation during the procedure. 26 had post dilation compared to 33% and 11% in the control group which mirrors instructions on utilization of the device. At the end of the day. This trial did not meet its pre specified endpoint of non inferiority. The neo aurate valve did not perform as well with regards to death stroke and re hospitalization as the traditional valves that we've used. Now at first blush, this is obviously a little disappointing. We were hoping this would show non inferiority and become part of the standard retinue of devices used boiling this down. When you look at death, when we look at stroke and when we look at re hospitalization, that same sort of trend line seen. But more careful analysis showed some interesting learning. First of all, safety end points were very similar between both groups. If you look, for example, the cardiovascular death rate was very low in both groups, stroke, especially disabling stroke was extremely low in both groups. When you look at the echocardiographic outcomes, what we see is the neo accurate, which is that purple line there performed well. In terms of gradient, it had single digit gradients which is in line what we would expect from the other platforms. Um so, despite limited operator experience with accurate neo, two early outcomes were encouraging. But the fact that it missed the non inferiority led to the question of what other factors could have affected those one year outcomes beyond the COVID related difficulty in enrolling and the limited operator experience. And a retrospective review showed something that I think is really interesting in that a lot of the discussion at TCT focused around and it was valve expansion. So in the stent world, we've long known that in order to get a stent to perform well, it must be fully expanded with post dilatation typically or at least ibis measurement to assure that the initial deployment expanded it nicely. In this trial, we saw something similar. What we saw is if you look at the red lines on the far left here, you see the convergence in a pie shape of those two red lines, looking at the major struts, this valve is actually under expanded. And when they went back and looked at the valve deployments, about 20% of cases had under expansion of the valve. As we see on these first two slides, we see that these there's a convergence and one other uh metric of this is the valve should be wider than the the bottom portion is tall. So in these three examples, we see this convergence of the flow lines and that shows us that these valves were actually under expanded. And on the top video, you see a fully expanded valve with laminar flow on the right side, that nice orange flow pattern giving good wash out on the left. You see an under expanded valve that has some pin wheeling and that creates on the right. What we see is turbulent flow and reduced washout and that reduced washout is theorized to potentially contribute to an increased risk of, for example, Thrombus formation or valve valve failure at an early stage. So that's something that we're going to be on the lookout for. And in fact, if we reanalyze the data and look at those that had an expanded frame, which was 550 compared to the under expanded frame, what we see is death stroke and re hospitalization were significantly higher in the group that had under expanded frames. And in fact, when we reanalyze in that, in that fashion, you see the top red line here is the under expanded Neo two S, the yellow line is the appropriately expanded ones. And the bluish line is the control group. And we see a much slighter difference which frankly would meet that non inferred endpoint if we look at expanded valves. So perhaps the biggest lesson ultimately, that was felt to be gained from this trial is it's not enough to put it in. We've got to make sure that we expand it fully and I'll just show one video. This on the left is the under expanded valve, then we balloon it here. You see the frame gets larger and on the right, we now see parallel struts. So you've given me a lot of time to go through in detail, these two trials and I'd like to hand over the floor now to Dr Cohen. So I'm gonna talk about the clear synergy oasis nine trial, which um is actually a trial that looked at medication effect, um which was surprising that we still do these types of trials. But um for um I'll briefly go over why this trial was done. Um We can go to the next slide. So um this is uh the Autumn Crocus, which is actually um where a culture scene uh occurs naturally. Um And uh that's what it looks like in a drawing and that's what it looks like in the wild if you have a garden, if you have these, I don't um we can go to the next slide. So colchicine is thousands of years old. Uh That's the Ebers Papyrus, which was um written about 1500 BC. So thousands of years ago, the Egyptians were aware of the properties of colchicine. Um And it was used really to treat joint swelling in the 18 hundreds, a bunch of French chemists uh were able to synthesize it. And uh we've been um using it as an anti inflammatory uh since then and uh you can go to the next slide. Yeah. So, uh it's actually named after Colchis. And if there's any Greek scholars in the audience, um you're aware that uh this was actually where uh Jason and the Argonauts landed. Looking for the Golden fleece, which is where um the autumn crocus sort of uh occurs naturally. You can go to the next slide and there's a picture of uh Jason uh landing uh looking for the Golden fleece next slide. So we currently use cardiovascular disease. Um as, as you guys all well know, we use it uh pericarditis. Uh We use it for Dressler syndrome. We use it uh post uh surgically for, um, to prevent a fib and it had been used uh post A as well to help reduce inflammation. Uh in terms of it's been studied in uh the stable coronary artery disease, secondary prevention uh population, um uh starting in 2013 with the lodo trial, which looked at 500 stable angina patients. This was done mostly in Europe. That's why it's a 0.5 mg of uh colchicine daily versus placebo. And the primary outcome was uh composite A CS death stroke. And this showed an absolute reduction in the primary end point. So things looked really good. Uh And we can go to the next slide. Uh This was followed up um later on with the Lodo 02 trial, which was larger, same population of patients. These are stable angina patients, secondary prevention. They haven't had any sort of intervention for half a year. Again, half a milligram of uh uh 0.5 mg of colchicine similar outpoint uh out uh end points. And again, it showed a reduction in cardiovascular mortality with the number needed to treat at 36. So, um this, that was uh here's the um the, the, the plot, these trials did do a 30 day run in um where they gave people colchicine to see who would wash out because obviously, as you'll see later on, there's a pretty significant percentage of people that develop uh a limiting diarrhea because of this next slide uh also has been studied in the post M I um uh population. This is the Col Cott trial which was done in 2019. So again, all of these were sort of right leading up to the pandemic, this was a larger trial. These are patients that had an M I but had normal ef so, you know, unstable angina non sting with no real reduction in ef um same intervention 0.5 mg of colchicine, similar end points. Um And there was again a smaller but still present absolute reduction in the primary end point. And in this trial was really driven by a reduction in stroke or a CS that required PC I. So uh we can go to the next slide. So uh there, there's our curve again and the curve sort of diverged relatively early on and then it's maintained over, you know, up to four years next slide uh in terms of acute coronary syndrome. So patients sort of immediately post M I. There was an Australian trial, the cops trial that came out around the same time, much, much smaller. But this looked at 0.5 mg B ID uh of colchicine uh only in the United States apparently has the 0.6 mg dosing of colchicine. And um I know you're disappointed, I don't know the answer to why that is. Um But so the rest of the world, I guess it's metric system or something, but the rest of the world does 0.5 mg. And uh in this trial, they did 0.5 B ID for a month, followed by 0.5 daily for, for total one year. Um And it looked at all, all cause mortality planned or unplanned PC I stroke and A CS. And again, there was a primary reduction in the primary end point. Uh So a at about, at around this time, many so uh societies, the European cardiology, Australian Society of Cardiology did have uh recommendations to use colchicine as a secondary prevention agent. And also um as a post M I treatment, it was, they were sort of class two B recommendations. So that's sort of what leads us up to um the clear synergy synergy trial, we can go to the next slide. Um Here's uh the slide, this sort of breaks down the um all, all the trials that we've talked about here so far. Um And sort of a meta analysis of those four trials, uh we can go to the next slide. Uh So clear synergy oasis nine. This is a uh uh so interesting this started prior to the results of the Col Cott trial. Um It was um to really to look for routine use of colchicine for the long term prevention uh of events. Um The trial design is uh it's actually a two by two placebo control trial. There was a second arm that looked at um uh Aldactone. Um It was 7000 patients. Um These were all patients with acute M I, they were getting a PC I, they were all treated with uh synergy stents. They were randomized within 72 hours of intervention and started on therapy and the mean follow up was three years and again, like D A mentioned this trial, same issues. There were a group of people that were enrolled prior to the COVID pandemic. There were people that were enrolled during let's call it the pandemic lockdown era if you will. And then there were people enrolled after that eased up, we can go to the next slide. Uh This show sort of the trial design. So 7000 patients and say where they were randomized into colchicine versus placebo and then they were randomized again to either placebo or Spironalactone. And then the outcome was a composite of cardiovascular death M I stroke or ischemia driver driven revascularization. Next slide. Uh briefly, these are the baseline characteristics. So, um again, uh you know, not a great uh distribution of male, female, but a lot of these patients were semi, a lower amount of diabetes than we typically expect. But again, this is a worldwide trial. So sort of the American is getting balanced out by, you know, the Swiss uh person having a semi. So um uh diabetes is a little bit lower than we would expect. Really. In our, in the United States, we can go to the next slide, um, medications at discharge. So all of these patients are on most of them, the standard medicines we put people on after they've had an M I. Um and uh no significant difference really between the two groups next slide. Uh PC I characteristics again, um, really no difference uh between the two groups, but most of these patients are getting a single stent. Um about half of them have some degree of multi vessel disease. That's man, that's going to be managed medically next slide. Uh So the results, um th this is the uh our curve here which showed that there really was no uh no significant difference in the primary outcome of cardiovascular death, M I stroke or uh ischemia driven PC I, which was uh somewhat surprising um Next slide. So, here are the uh abso uh here are the percentages when you break things down. Um Really any way you slice this trial, um All of the pres specified uh subgroups when they were ana analyzed all of the subgroups that weren't pres specified no matter which way they cut this trial, they couldn't find any statistic uh benefit for col scene over placebo. Um And, you know, here, here are the main ones that are, you know, the hard ones that we actually care about death and M I uh stroke actually, um there was no significant difference either. Next slide, here's the on treatment analysis. Again, really things were identical between the two groups. Uh There was a trend towards lower uh non cardiovascular death. Um in the colchicine arm. Next slide, adverse events are probably what you would expect for this group. There's a statistically significant uh uh increase in diarrhea amongst the patients that were treated with colchicine, which was similar to uh which was more pronounced, I should say uh in this trial than previous trials. Um looking at colchicine. Um and that is most likely related to all of the secondary prevention trials had some type of uh run in period where patients that didn't tolerate the colchicine due to diarrhea were washed out. Uh next slide. So, results, um you know, this was, did not show the benefit uh that uh that was hoped for. Um, we had uh the sort of the hope for the trial was that this would this randomized trial could really uh bump up the level of evidence for the use of colchicine to uh class one indication. Uh Obviously that's not the case. Um And I think that in general, um, you know, I think that the jury is probably still out on the use of colchicine in terms of, is there a right population for it? Uh This trial is certainly the largest and longest trial looking at um routine use of colchicine for prevention of events in a post uh a CS population and it looks like it's not gonna be a, be uh routine use is not ideal there. However, I think that we probably need to have a similarly sized trial looking at uh secondary prevention. I think that uh I think that's my last slide. Thank you. Thank you. All right. So, uh up to this point, we've, we've heard uh uh three negative trials uh but all very, very important as far as answering uh pending questions that we've had with at least within structural heart. Uh the, the third valve platform, it was gonna be our fourth valve platform with Boston scientific is and now been proven to be uh not non inferior to a typical valve platforms. So that fundamentally means that we're gonna go forward uh very likely with three commercial uh valve platforms. Uh We've long used Orbital Arrey as one of our main stays of uh plaque modification that's uh very likely to change after this. And then we've been looking for roles for colchicine. It's anti-inflammatory effects in all different forms of uh stem and non ST elevation A CS. And uh this, this certainly answered some questions about that. Um But uh in a positive realm, we did have uh uh arguably the, the largest trial that's come out in structural heart in the last few years, early tavern and that was released at TCT this past uh few weeks as well. So I wanted to run through that trial, the basis for it and what the results were because they're pretty uh significant. So, first and foremost, most people know this, but our current clinical approach is that any patient uh needing a VR has to have both a certain severity threshold and have symptoms. It's not enough to have one or the other. We uh our guidelines dictate that if a patient is presymptomatic, uh that we, we actively surveil them for symptoms with guideline based recommendations that their next follow up appointment is in six months, these guidelines were developed when uh we had a VR really existing only in the form of saber and patients rarely were reoperated on after the age of 75. And so, uh as cardiologists, cardiothoracic surgeons waited as long as possible uh because we know the valves only lasted a mean of 13 years. Um And so these guidelines were based on two different thresholds, both severity and symptom status. Uh But we've long been concerned that we're waiting too long, uh particularly as we now have less invasive uh therapies that can be applied to younger patients. But more importantly, we have uh those therapies available for when valves do degenerate. Um uh for instance, valve and valve tabor has become the mainstay of treatment for SPD and has allowed us to push that bar a little bit lower as far as uh both severity and uh symptomatic status because uh we now have a way to rela the valves that doesn't require radio open heart surgery. So there's two trials designed in, in the current modern Tavern and modern A VR era. Uh to address both of these, both, uh early tver was to address uh symptoms versus not symptoms. And progress was uh is meant to address a severity threshold. So, next slide and so ctera we were one of the uh leading enrolls uh in this trial. Over the past several years, we had 15 implants among 75 centers. This trial was designed uh for a 1 to 1 enrollment of about 450 patients in each arm. And basically, if a patient had severe uh aortic stenosis, they got randomized 1 to 1 to either a clinical surveillance or to go straight to tab or even before symptoms. Uh importantly, uh to, to provide some objectivity uh to this uh enrollment required an exercise treadmill test to prove their asymptomatic status. And importantly, a third of the patients screen failed because when we put them on the treadmill, they were actually symptomatic. That highlights to me that even at uh uh 75 of the best valve centers with clinicians that are, are tasked with taking care of aortic stenosis. And one third of those patients, we can't even get their symptomatic status uh correct. And, and importantly, the guidelines dictate that the pre symptomatic patients are followed every six months. And what you'll see from this trial data is that a lot of these heart events happened before that guideline based recommendation. So next slide, this is the need of it. Um And so what we, what we did is we saw even with a uh sts of 1.8% these are low risk modern day patients, 83% of them, almost 84% were considered low risk. That if you take this, these two approaches and you randomize them, 45% of patients that were undergoing active surveillance had a major adverse coronary event that one year compared to only 26.8% that went ahead and had their t done. Uh This uh occurred over a median follow up of 3.8 years. Um and 80 per 7% of the patients under their surveillance arm during that time, ended up getting aortic valve replacement. And this is driven mostly by unplanned hospitalization to cardiovascular cause. It's not a benign thing. We don't expect to see deaths this early on necessarily or strokes this early on. But you can start to see separations in the curves already. Um The number needed to treat is only 5.4 which is as far as the treatment effect. Pretty significant. That's to prevent mace that one year. Uh Again, just a, a reminder we do Milos for a number needed to treat of six. We do you know primary PC I for a number of needed treat up between eight and 10. And so there's, there's a lot of uh significant treatment effect here as far as the, the uh uh size of the treatment effect. Here's what I thought was interesting. 100 and five patients, almost a quarter of the patients that we had assigned to the Clinical Surveillance arm converted to TAVR within the first six months. So before their guideline based next uh appointment, nearly a third of those patients were hospitalized with severe symptoms and three patients died of sudden cardiac death. Go to the next slide. This is looking at some other uh treatment effects. They looked at symptomatic status uh when uh patients had their aortic valve replacement. Um and then some uh measures of both symptoms and LVL A performance. There's a variety of ways that went through this with strain and LV mass index as well as L A volumes. But some of these uh uh effects that will be studied in progress as far as early myocardial dysfunction and scarring, diastolic dysfunction, atrial fibrillation. All these sort of softer associations will be studied more precisely in the severity threshold trial. Next slide. So the bottom line is that this is paradigm shifting. We we wait for symptoms and aortic stenosis and we're causing harm. 25% of the patients waiting for symptoms ended up needing their valve done before the first guideline directed follow up appointment. 35% of those hos uh patients were hospitalized with severe symptoms. Current estimates are that we reach only uh less than 20% of eligible A VR patients. And that's with the current guideline based severe plus symptoms, we now have an obligation to go out into our communion screen for severe asymptomatic A S patients because they have such a decrement and there are adverse coronary events at one year. Uh when we do active surveillance, it's important to note that a third of those patients who put them on a treadmill would already have symptoms as well. Community screening will result in our earlier treatment. That's better outcomes for our patients. Um We know that our inpatient tab rates or a rates are all reflective of when we meet these patients and their natural history. We go out in the community and screen more and start treating patients at an earlier point in time. We're only gonna benefit uh the overall uh natural history of this disease. Uh At least in our community slide to then Deepak uh uh mentioned, we, we presented on uh dos and I wanted to take this as a, a chance to just show where we're at with some of these things and to encourage uh that if you have patients uh coming to our valve center, uh referring or invited to these uh valve selection and valve therapy disposition disposition meetings. Uh But we've uh partnered with DOSSI which is a complex uh computational modeling, preprocedural simulation uh planning company that uh does TVER simulations and advanced structural heart simulations to help guide complex procedures. So, we presented uh one of our cases at that uh at TCT in that form, you can go to the next slide, but just to highlight where we're at, this is why we're presenting at these meetings in this fashion as we redesigned our valve uh conference two years ago, that's now going to be in the education center uh starting in January uh where we'll have coffee and breakfast. It's modeled after tumor board review between 2030 patients. Uh When you refer a patient to the valve center, when you talk to Amy Cantor just mentioned that uh you would like to be invited to that uh valve conference or attended and your patients, you can see how the selection process is made. I get CME for attendance if you come in person. And then uh as mentioned, starting in January, we're gonna incorporate advanced preprocedural uh uh computational modeling into every one of these uh valve selection uh decisions. Since uh last year, we evaluated over 1000 patients in this current model. Next slide. And that's led to a very precise understanding of why we make uh certain decisions as far as self expanding valves versus balloon expanding valves. And our heart team has been asked to present on this, this uh process because it's so uh patient centric visualized in the setting of having uh 500 tables a year and having maintain all that throughput and get uh uh good outcomes. Individualizing therapy can be very difficult. And there's 16 to 20 different uh factors that weigh into why we make certain decisions as far as who gets an evolut, who gets an avatar, who gets a SAPIEN. And we've ironed those out through the past two years and defined them better. But with a lot more precision, we're planning to incorporate this computational modeling. So next slide, this is uh one of our patients that underwent a valve and valve mitral. Uh Last week, you can see uh with this software, it takes a patient's CT scan and instead of just putting in virtual geometry and embedding it on top of a static CT image, it actually incorporates tis tissue characteristics, the alloy characteristics uh and tissue deformation to simulate the biophysical process. When you implant a valve, I had uh next slide, I had a referring reach out to me last last week and said, hey, um you know, where, where are you guys at with bic cuspid valves and TVER? Um You know, I see that that a lot of people are doing BPI uh TVER. And how are you making those decisions? Is it still an obligate surgery? Um I was reading that a lot of people are doing them with TVER. And the short answer is that there's a big gray zone here, about 15 to 20% of our tas uh are in some variants of B cuspid patients. Um But these are the patients that are gonna require more precision in our dis in our therapy disposition. Our selection, this is using dossi on a 72 year old bics aortic valve patient that uh we worked up last month. Doctor Kemp and myself, you can see we can take both different valve platforms and implant them in this patient's unique anatomy. More importantly, this DC software has incorporated advanced uh uh artificial intelligence and machine learning to incorporate prep prediction, basically modeling of different factors that would, that would put during that procedure, coronary occlusion, annular rupture risk, pacemaker risk, PV LS which para leak and hemodynamics can all be predicted. And you can differentiate those based on the two different valve platforms. More importantly, the machine learning has actually taken the input and the output characteristics of this has been able to find predictive uh variables like this DLC over D that have RFC curves and predictive modeling that's uh dramatically 2.5 times better what we currently use in structural heart. So this is an actual patient, an actual real time where we're making decisions on which valve platform we're going to use based on their anticipated outcomes. And we're going to be able to define these with each patient that goes through our process and the next slide. And then this is what it's going to look like in our valve conference. So when you have a patient come through with AC T scan uh in valve conference, I'll now be able to take uh their individual anatomy and predict exactly where we're gonna put in each valve platform and make a decision based on the outcomes predicted from each of these uh virtual valve implantations. You can see this is us putting in a uh evolut in a SAPIEN at implant depths between minus two and minus four. You can see it'll predict where the uh stress points are on the annulus with each of those platforms, where the annular uh rupture risk is where you're gonna have issues of commercial alignment and coronary access, where you're gonna have issues with uh eccentricity and valve under deployment. More importantly, what you see there is they're implanting the second valve. Um So you can plan for your procedure in 15 years, 10 to 15 years and they're showing you the annular rupture heat maps uh where you, you have pressure points. Um So this allows you to plan for at least two valve procedures and how to often mitigate the complications inherent with each of these um based on uh specific characteristics which within that patient's CT scan. And so this will allow us to be incredibly more uh precise in our planning and sophisticated and allow us to maintain that patient centric focus and individualized therapy to try to make already low risks for these procedures even dramatically lower. Um But allow us to take care of patients in this community for, for decades and not just through their first valve uh iteration, go to the next slide. That's all we have any questions. Published December 2, 2024 Created by Related Presenters Luke Kohan, M.D. CardiologyInternal Medicine View full profile Matthew Summers, M.D. Sentara Cardiology Specialists View full profile
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