Join Valentín Fuster, MD, PhD, MACC and a panel of experts for a discussion on the top late-breaking clinical trials released during the ACC 2023 Conference.
Chapters (Click to go to chapter start)
Introduction COAPT TRILUMINATE Pivotal EVOLUT Low Risk CLEAR Outcomes STOP CA FREEDOM COVID BIOVASC STELLAR A DUE & Other Trials Panelist’s “Best of ACC.23/WCC” Selections
I am Ballantyne Foster from New York and it's a pleasure to have this session this morning following the scientific sessions of the American College of Cardiology in New Orleans. As usual, we're going to present a number of topics that we think were important, particularly related to trials. And I have three experts here who are going to help us in judging the outcomes of such trials. Here on my right is Dr Pamela Morris, who is the Palmer and Down chair in Cardiovascular disease Prevention and Director of the Saints Heimer Cardiovascular Health Program at the Medical University of South Carolina. We have also Dr Patrick Parrino from New Orleans, chief of the section of thoracic and cardiovascular surgery at the Ochsner Health System. And then in my left, I have Dr Edward Fry, president of the American College of Cardiology and Chair of the National Cardiovascular Service Line Essential Health. Well, it's going to be interesting discussion here. We have a number of studies that were presented and hopefully we can make sense about the four main topics that were presented. First of all, Bob low heart disease. Second, about metabolic diseases. About third symbiotic problems and forth about pulmonary hypertension. So we are ready. All right, let's move on. Let's start now with the bubble a heart disease. And the first study that we are going to discuss is the co op study, the co opt investigators. This was published now in the New England Journal of Medicine and is entitled five year follow up after transplanted to repair of secondary mitral regurgitation. Uh the presenters Dr Greg Stone and we are all familiarized with the co op study, but I will give some background. Um The court compared with optimal medical therapy with trans category H two H repair and was safe and improved two year outcome in patients with heart failure with secondary mitral regurgitation who remain symptomatic despite optimal medical therapy, whether these benefits are sustained with long term follow up has not been reported. So the report was about a two year follow up and here we have the five year follow up. Let's see what the report says. They randomized 614 heart failure patients with moderate to severe or severe secondary mitral regurgitation could remain symptomatic despite maximally tolerated guideline, directed medical therapy. And this was compared with medical therapy alone. The study was performed in 78 sites in the United States and Canada. And the primary effectiveness and point was of all hospitalizations for heart failure through two years of follow up. Final follow up through five years is what is reported today. The annualized rates of heart failure, hospitalization through five years were 33% per year per patient in the device group. And 557% per year for patients in the control group. Very significant with the hazard ratio of 0.53 all cause mortality through five years of Curing. of the device group versus 67% of the control group. And then finally death or hospitalization for heart failure through five years, a curing 73% of the device group versus 91.5% of the control group with the ratio of 0.53. So, in conclusion, in patients with heart failure and moderate to severe or severe secondary mitral regurgitation to remain symptomatic. Despite guideline directed medical therapy, transcanada's H two H repair of the mitral valve was safe and reduce the rates of heart failure, hospitalizations and all cause mortality through five year. Follow up. I could begin asking a surgeon what the surgeon thinks about all of these, but I like to prefer to talk to you. What do you think about this study? Well, I think it's a confirmatory of the durability of the initial positive results. Um I think it's also um a testimony to the fact that uh trying to do trials when so many things are changing at the same time, some of the follow up of this trial took place during COVID and we know that that has had a significant impact in other trials in terms of the measurement of hospitalizations for heart failure, that those hospitalizations had been reduced by the intention of keeping people out of the hospital during COVID. So the fact that there is this uh significant differences, probably actually underestimates its, its uh its value. Um And we also had the the evolution of guideline directed medical therapy for heart failure during this period of time with the on boarding of S G L T two inhibitors, which probably were used uh used in the latter part of the of the follow up. So I think it's uh it's uh it confirms the fact that this is an important intervention for patients who have truly failed guideline directed medical therapy and gives us some Uh some confidence that that result is durable, but these are very very sick patients given the fact of how many have either died at the end of the trial or continue to have need for hospital question, Pamela, you know, the data is 91% of the control group patients and 73% of the device group patients. Kita died as I had mentioned or being hospitalized for heart failure within five years. So we are dealing with a very sick population though, that's, that's one of the most important pieces of data I think that comes out of that study is, it really confirms how incredibly high risk these patients are. Certainly the benefits are that these peixe did have at least some prolonged survival at five years. But what a high risk group of patients, I have the feeling what we are doing to improve the quality of life perhaps rather than paying too much attention into mortality. Patrick, you're a surgeon. What do you think? Well, I have several thoughts about this and I think primarily I think this is a terrific thing. Um, you know, there's just this awfully tedious cliche that for secondary M R, is it a disease of the valve or a disease of the ventricle? And we've all heard that ad nauseam. Um but that's clearly what this is. And for these patients were not looking for a 10 year result right there. If this, many of them are dead at five years, they're all gonna be dead at 10 years. And so looking for an intermediate term result, the clip is a great solution for those patients. And in particular, where we found this to be helpful as is a bridge to transplant or as a bridge to L VAT. If these patients can be palliative, essentially with this clip, then that buys them some time for G D M T. And then when they do eventually progress, uh the L VAD operation is much more straightforward with a clip in place. Or the heart transplant operation is much more straightforward with a clip in place as opposed to a valve replacement, which is probably, I hate to use the term overkill for these patients because they don't need that durable of a result. The clip is a much better solution. So basically what we are saying is a plus study. And I think quality of life, I think is important, but certainly this is a very sick population. Well, with this conclusion, we have more to say now about Babel a heart disease. Let's move into the tray, caspit valve. What do you think Patrick? This is a, is a new field is indeed the trick. A spit valve has been forgotten. Uh Not completely forgotten. All right. All right. Well, let's let's let's now go into the study we're going to present now, the trial illuminate study. Uh This is a study that is entitled as published in the New England Journal of Medicine. Today is transplanted to repair for patients with Tricastin regurgitation. Dr Paul from Minneapolis was the one who presented the study. Let's perhaps go into some background of the street Caspit valve. I don't know. I evolved over the years. Always thinking that the Drake a spit valve is something that you deal with. After mitral valve. At the time of mitral valve intervention, patients have hospital visitations secondary to pulmonary hypertension. We have to discuss in a moment who are the patients that are being treated here. But let's go into into what is historically important is both American and European guidelines. They say three caspit valve surgery class one recommendation only for patients with severe tree caspit resuscitation at the time of left sided surgery. This is what we were saying. The second point is that in 2021 the E S C E A C T S guidelines additionally includes symptomatic patients with severe isolated primary trade caspit regards irritation without severe right ventricular dysfunction as a class one recommendation for trick a spit valve surgery. This is closer to the study that we're going to be represented in a minute. And the the problem has been, it seems to me at least what you read in the literature is the trade caspit surgery carries some high mortality, 8 to 10% maybe this is exaggerated. But this is what has been historically, the thought is you keep conservative in the tri caspit valve. Anyway, Patrick says he's, he's in this agreement with that. Well, he's a good surgeon, But the reality is that in the literature, they involve intervention as an isolated is some problems with mortality. Well, recently treatment of the hospital visitation with transported their H2A's repair has emerged as a safe and potentially effective therapy. And let's see what this study is telling us because it's a unique study, perhaps the first one in a large number of patients. And let's now describe what this study is all about to illuminate. Pivotal is the first prospective randomized control trial to assess the impact of trance category. Intervention for Trey caspit resuscitation Uh investigators enrolled patients with symptomatic severe tree caspit resuscitation. At 65 centers in the United States, Canada and Europe. The patients were randomly assigned to either trick hospitals, catheter H two H repair or medical therapy. The primary endpoint was hierarchical composite of all cause mortality, hospital surgery, heart failure, hospitalization and quality of life. By the K C C C Q approach. The Kansas City cardiomyopathy questionnaire, 350 patients with a mean age of 78 years, 55% were women were enrolled has scattered. The tree caspit repair was highly effective with moderate or less than residual reverse station at 30 days post procedure. 87% in the in the intervene group with good three caspit application versus 4.8% in the control patients. The primary endpoint of the trial was met indicating significant clinical benefit of this procedure in patients with tricastin visitation. The benefit was predominantly related to symptomatic relief and quality of life improvement. In fact, this is a short follow up of one year. So basically in conclusion tree caspit uh approach with this non surgical intervention is safe and effective for patients with severe tree caspit resuscitation in associated with significant improvement in quality of life. Pamela. I have a few questions about this study. First of all, and I had to ask the investigators this how many patients actually were previously operated for mitral valve disease or intervened with H2H approach 20%. So we have 80% of patients who have what appears to be isolated resuscitation. What I'm saying, these patients are not common. In other words, I want to be sure that people don't think not recasting regurgitation, we're going to do this and that. In fact, I don't think it's a large population. What do you think? I think your point is well taken. I mean, this is, this is that will be one of the challenges of implementing this procedure is I think really identifying the right patient for the procedure, particularly in light of the fact that The benefit is largely driven by quality of life. So I think careful patient selection is going to be one of the most important aspects, Patrick, what do you think these are patients with caspit prolapse? Tell me, what kind of patient do you think is here? Because patients didn't have hypertension. The pulmonary artery pressures were less than 70. I don't know if they had metal valve disease or not is unclear. But what do you think? I think it's a godsend. Um When I was at Cleveland Clinic, my friend Ed Magee looked at the Cleveland Clinic data for reduced renata me and try to spit valve operation and the mortality was 33%. It's awful. And one thing they didn't, at least in the limited stuff that I saw comment upon was the degree of the paddock dysfunction that these patients have. But many of them have significant paddock congestion or full on, you know, old term cardiac cirrhosis. And so they're awful operative candidates and they can be quite symptomatic with severe tr and so I think in particular patients who have had previous stern, ah, to me, this is a wonderful solution from a symptomatic approach. I'm not so sure if they have in common in other valvular disease, if it's the best thing, but for isolated tr especially in a post operative patient, I think it's wonderful. I think that we are talking again about improvement in quality of life. I suspect that in a long follow up, maybe these patients will live longer. But I think the effects on quality of life are probably very significant here. I would agree. I mean, the KCC Q and they used a very aggressive endpoint of 15 Uh points of improvement and most people seem to consider 10, 10 points improvement as being a a marker of improved quality of life. So I would agree and and isn't that what we do a lot in practice, we really are focused on making people feel better uh, as as their, their most valued outcome. And it's great to see a patient reported outcome be really part of the, really be the pivotal part of the trial. So it seems to me that we are dealing with two studies, one in the mitral valve with secondary mitral regurgitation, and this particular one in trick a spit valve, most of the patients I suspected primary caspit regurgitation, which what we are really coming up after this meeting is quality of life may be improved. Let's see what happens long term in terms of mortality. Is this correct? Yes, I think so. I'm wary of any tier approach that doesn't obviously include an annual plastic because for most valve repairs, annual plastic is a really important component of durability. So we'll see how it does over time. Can I ask your prediction about the spit valve? Do you think this is going to be the key technology because there are so many other non surgical interventions with now evolving. Do you think this is going to be a critical one? I think it's gonna work well over the short and intermediate term, long term. Again, without an annual plastic band, I'm not confident. But again, for this patient group of 78 year olds were not looking for a long term result. I would be interested to, to ask about, you know, one of the um exclusions or the group of patients who undergo mitral um edged edge repair, exclusion of people who have severe tr does this now open the door to bring that group of patients into, you know, being candidates for, for mitral? I think. So, I think in particular for cardiomyopathy patients again, is a bridge to something else, whether it's transplant or if they're later in life is a quality of life. Measure a double tier approach for both valves would be a reasonable thing. Well, let's move on into the third topic and bubble a heart disease. Now, we are moving to the aortic valve. What a field with a heart disease? A few years ago, we talked about rheumatic disease. Is that right? Mitral stenosis and then certainly aortic stenosis in the elderly here today is just like an explosion. Very positive. Well, let's go into the third paper and it's about the low risk stubborn group and it's entitled Three year Outcomes after trans catheter or surgical aortic valve replacement in low risk patients with aortic stenosis. This was presented by Dr John Forrest from the Yale University School of Medicine in New Heaven. Well, you know, we all have been worried about moving into low risk patients with this kind of interventions and we'll have a discussion about. But let me introduce the subject and much of the data supporting tower has been in patients with increased risk for surgery and recent data on low risk patients populations for those promising short term outcomes is evolving. But with some worries, there is a lack of intermediate or longer term data for such patients. And let me see what this study is presented today is going to tell us is a three year follow up. Let me let me focus into the study, the absolute low risk trial, randomized patients with severe aortic stenosis who had an indication for aortic valve replacement and we're low risk of surgery to either Taber or surgery. All patients in the glorious trial have now completed three years of follow up. In fact, if I recall they published their data over two years of follow up, this is a three year follow up. Well, let's go into the details of the study. Low risk patients were randomized to tamper with a self expanding super annual above or surgery. The primary endpoint was all cause mortality or disabling a stroke. And several secondary endpoints were assessed at three years. Many, many groups participated in this study, 80 86 sides in seven countries. The number of patients that were randomized were 1,414 patients had a mean age of 74 years and 35% were women at three years. The primary endpoint a cure in 7.4% of the tower group patients and 10.4% of the surgery patients with a P value of 0.0 51 close to significant, not significant. Well, anyway, this is the data, the incidence of mild para valvular resuscitation in 20% of the tower group versus 2.5% of the surgery group. I have to say. However, that significant para babulal resuscitation was equal in both groups. This is very mild and the pacemaker placement is important. 23% in the tower group versus 9% in the surgery group. Uh there were anyway, this is the data. So pacemaker is an issue. Patients when they went over had significantly improved both thermodynamics. Well, I'm in gradient of nine of mercury for tower 12 mm of mercury for surgery is a short follow up. And no, I don't think this is important at this point. But the conclusions are that within the absolute low risk study, top three years showed durable benefits compared to surgery with respect to all cause mortality or disabling stroke. Patrick. This is important but always bring some worries. And that is the enthusiasm for non surgical interventions is getting now into younger people with severe aortic stenosis. But what is the outcome? Well, as you are feeling about this concern, I think low risk doesn't necessarily mean young. There's plenty of low risk octogenarians and my concern. I think this is a wonderful solution for patients in their seventies and their eighties. I think it's a great thing. But having done operations for patients in their fifties who received trans catheter valves, You're kind of kicking the can down the road that that's, you know, device, the order grows into that device. And often when we re operate on those patients or operate on those patients, it necessitates a root replacement rather than a valve replacement, which is known to be a higher risk operation. And so I would be cautious about equating low risk to young because those are not the same thing at your age 50. I wish. Tell me a surgeon comes to you and interventional is and says, you know, your aortic valve has to be replaced. You are in great shape, but you have severe aortic stenosis. What would be your answer based on the study? Well, I'd want to understand my relationship with the person having the discussion with because I think this is critical the sequencing issue. Thinking ahead. Hopefully, you're talking about 30, 40 years of Having an active life. Beyond that, you'd really want to understand what does the surgeon or the interventional cardiologist, what are they going to say to you in terms of what is the plan down the road? I want to know. So in 15 years, what's going to happen? What's in 30 years, what's going to happen? And I would, that would be a very important shared decision, making moment. Pamela, what is your thinking? You know, I think two thoughts with this study. One is that it really highlights the importance of the structural team and the importance of the surgeon and the interventional structural cardiologists to really adequately communicate the long term, the long term or potential outcomes. The other issue is really being honest about the risk of a permanent pacemaker. So you maybe don't get a surgical procedure, but you end up with a permanent pacemaker. So again, I think the team approach and the importance of shared decision making that's been a dramatic evolution and our management with these patients. So I think we can summarize, I don't know if you are in agreement that we have to go forward on every aspect of Babel a heart disease and thinking about non surgical intervention. But I think this particular one, I think we have to be cautious is not correct. Yeah, I think we already had information that these devices are, are fairly durable. Certainly in this relatively short period of follow up, it all comes down to. And it's interesting that the average age of the patients in this trial was 74. So that's a very different conversation as Patrick was saying, than if you're 50. But this important Patrick, what you said, I think that for the very elderly patient, this may be a procedure h 80 85 even age 90 and and so forth. Well, let's see how this field is, is, is being approached in the near future. But anyway, this is the third, three year follow up. Well, we are done with valvular heart disease. We touch into three valves, we miss one is pulmonary valve, but let's forget for today. But these are interesting studies and now we are entering into a new topic is uh we call metabolic diseases, just something that you like Pamela. And but let's let's start with an interesting study was the clearest study. The clearest study entitled Acid and Cardiovascular Outcomes in started intolerant patients. The study was presented by Dr Stephen Neeson uh from the Cleveland Clinic. And it's interesting and this is in patients who they were intolerant to statins mainly because of the problems that we know the muscular problems and so forth. Let's now give some introduction to this particular study. First of all, what is Ben Ben Pedrick Acid? Actually, this was a proof I think by the FDA about, about three or four years ago. Is this correct? And this is basically targets the synthesis of cholesterol more approximately than the enzyme, the enzyme reductase. That well by we you use the statins just to prevent the synthesis is more proximal. And what is interesting is that starting work in many organs. And actually, one of the organs that works is in the muscles where this drug actually doesn't get there. All the metabolic aspects are in the liver. So it's interesting theoretically speaking, the patients who are intolerant to statins because of muscular problems. At least this drug, again, theoretically speaking, could be of help. And there are some preliminary studies and this is why the FDA approved the drug showing that this could be an alternative to patients who have started intolerance. This being said, let's now go into the details of the study. This was a double blind randomized placebo controlled trial involving patients who were unable or unwilling to take statins owing to an acceptable adverse effects, so called starting intolerance and head or were a high risk for cardiovascular disease. So these patients were a high risk for cardiovascular disease. This is important oral like acid, which is 100 and 80 mg daily or placebo was the randomization all about the primary endpoint was a four component composite of measure adverse cardiovascular events. The finance debt from from cardiovascular causes nonfatal myocardial infarction, nonfatal stroke or coronary revascularization. 1200 sites participated in this study, 32 countries and this is a very large study near 14,000 patients participated. Well, the median duration of follow up was 40.6 months. The men LDH cholesterol level at best line 139 mg per day for DL in both groups. And after six months, the reduction in the level was greater with Cassie than with placebo by 29 mg per DL. And the observed difference in the percent reduction was 21%. The incidence of a primary endpoint, which is the importance here was significantly lower with than with placebo. 11.7% was 13.3%. So bmp delicacy had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes and then from any cost. So the incidence of gout and collect diocese were higher with than with placebo 3.1% vs 2.1%. And I'd like to conclude by saying that among starting intolerant patients reductions in LDL cholesterol levels with like acid were associated with a lower risk of measure adverse cardiovascular events. This is basically an interesting study I had had a question here, there were foreign points or composite of foreign points, but it seems that revascularization was a critical endpoint that we have to look for. And also it appears myocardial infarction. The other endpoints with bad death or stroke didn't play a role here. So tell us about the study. Well, I think it's impressive to actually see that level of improvement in terms of revascularization. And am I in a relatively short period of time, sort of supports our feeling that the lower the LDL cholesterol, the better the clinical out the outcome will be and reinforces the idea that we're seeing plaque stabilization, which would really be the underlying mechanism, driving urgent revascularization and myocardial infarction. I think the biggest point here, I think I'd be interested to hear what Pam has to say. I think we perhaps now in patients who are truly statin intolerant and that that's a question Um is that now we do really don't have an excuse to just say, well, that's too bad, you know, good luck to you. I think now we have an imperative to, to really try and address their LDL cholesterol from your in this field. The drug was approved in 2020. Are you using it? Yes, I am. You know, the biggest obstacle to this to this drug is really just the cost issue. That's the biggest issue is really getting it as with most payers initially when a drug is released, even when you prescribe it for someone who need the FDA approved indications. It can be difficult. It is interesting, it can be very effective. And when used in combination with the, you really do get reductions that are quite similar to high intensity statin. So it has been very beneficial. It also provides an option for patients when you're really on that edge between an injectable therapy or an oral therapy. The combination really does give you an option for patients. So Patrick, did you hear about it before? And I thought it was interesting um because I tried to look it up and I'm not aware that it has some of the anti inflammatory properties that the statins have. So I thought it was interesting that it provided the same kind of stabilization without the anti inflammatory piece. But from a surgical standpoint, you know, it's exhausting having people tell you think the veins are all gonna wear out in 10 years because all that data is prior to even the advent of statin therapy. And so to have something else that improves the durability of vein grafts is a great thing because that's a palliative operation and the more effective that pal e ation is the better. So I think it's terrific that this is an option for people. So a good option but somewhat expensive. Is this a good conclusion? And hopefully though with this study, hopefully with the results of this study, this will end with time, this will become we now have outcomes data and hopefully it will be easier to get it approved. And hopefully with time the cost will begin to come down much like the PCSK nine monoclonal. This is through, through pressure to industry. Yeah. Yeah, definitely. But in the discussion, it was very interesting. One of the topics that came up is that, you know, is there a concern that there is now too easy of an off ramp in terms of defining somebody who is statin intolerant. You know, how hard do you really work at that point? Okay. Well, thank you very much. And now we are going to the second paper on metabolic aspects. Here is the stop see a trial is starting to prevent the cardio toxicity for from anti cycling's. The paper was presented by Dr Thomas Neyland from the Massachusetts General Hospital in Boston. And let's see what this is all about. Well, we know about the cardio toxicity of anti cycling's. Uh this drug, these drugs I would say are used for several cancers, breast cancers, lymphoma, particularly leukemia in sarcoma. And uh it's certainly a concern to the cardiologist because they, it causes cardiac injury and which is can be very significant. Well, in any case, there is some experimental data, retrospective studies pointing out that the statins could be helpful in preventing the effects of entre cycling's into the myocardial. And this is the study, perhaps the largest study on this topic with the use of atorvastatin. It's interesting that there is a recent multi center randomized trial of atorvastatin versus placebo with a 24 months of follow up and left ventricular ejection fraction did not change was 58% in the placebo group and 58% in the atorvastatin group. And this is an interesting piece of information as we will see in a moment. So we are dealing with multi center randomized double blind placebo controlled trial in patients with lymphoma. Over age of 18 years, there were nine centers in the United States and Canada that participated in the study. So let's see what the details of this study were all about. Well, first of all, the primary outcome is interesting, the proportion in each group who had a decline in 11th rejection fraction of more than 10% to less than 55%. So the ejection fraction has to drop more than 10%. And finally, less than 55% should be the ejection fraction. A secondary endpoint is the same. But instead of 10%, we talk about 5% and you have to drop to less than 55% ejection fraction. These were the endpoints safety and point at those events of of specific interest. Well, what we are talking about, we're talking about 300 patients, they were randomized into 40 mg, 150 patients, 40 mg of starting per day and then the 150 patients were allocated to placebo control. The follow up 12 months Results. The first look is very impressive. The incidence of the primary endpoint and 12 months was 9% in the starting group. 22% in the placebo group. Great results. You go into ejection fraction and then the situation looks a little bit different. Pamela, You start with an injection faction that are starting group of 63% and you drop it to 59% In the Placebo group. You start with 63% and you drop it to 57%. So we are talking about ejection fractions that we feel comfortable. No, in our practice. And then the difference between one group and the other is 1.3%. So the question is that the summary of the conclusions of the study, which they go to the primary endpoint, the prophylactic use of starting over 12 months was associated with a lower rate of cardiac systolic dysfunction. These data support the use of the term a starting among patients with lymphoma being treated with anti-clcling's where prevention of cardiac systolic dysfunction is important. Have questions about these conclusions. What do you think, Pamela? Well, you know, it's interesting because the study was not actually powered to look at the clinical results of a reduction in ejection fraction. So not being powered to look at heart failure outcomes limits what I can take away from this clinically. It also opens up for me as a prevention enthusiast and using statins. It opens up a whole new group of patients for whom I now need to be concerned about statin intolerance and statin tolerable bility and optimal dose ng other cancers. It is, it is of interest so hard to know what to make of it in the setting of no clinical understanding of what that modest ejection fraction change means Patrick, you're a surgeon, we talk about the ejection fractions, you know it are reasonable. So what do you think about this, the information of this uh this paper, I want so much for it to work, but I don't think that I can say that it works based on that paper. Um Those are very difficult patients when they present with heart failure after having been treated successfully to one degree or another for malignancy. And our our opportunities are limited as far as Elva and transplant go with this patient population. So I would really like for this to work, but I can't read that paper and be confident that this is gonna work based on the data. So raises more questions than it answers, I think. And uh as, as Dr Morris was saying the issue of uh not knowing enough about the clinical outcomes, I mean, the trial was really looking at heart failure, we know that half of heart failure is preserved ejection fraction, heart failure, right. And then half has reduced ejection, heart failure. Um I guess, and in the trial, we also saw one of the questions that came up was the dosage of the anti recycling was relatively high. And in the subgroup analysis that looked like if, if you were below a certain level, you didn't derive any apparent benefits. So maybe this turns out to be something that would be helpful in those higher risk patients getting a larger dose of the anthrax cycling. I guess we also have to turn it around and say all of these patients had some reduction in their ejection fraction. So there's, you know, there's something going on there and if the downside of atorvastatin is minimal or zero, maybe in terms of the overall management, these patients, it's not an unreasonable thing to think about, especially if they're going to get a high dose of the anti cycling. I also still have questions about this whole concept. Mechanistic Lee in terms of yes, there are reductions and inflammation reductions in HS CRP. But mechanistic Lee, what do we think is going on here is still unclear to me. I suspect I suspect we'll see some publications further from the MRI analysis to see if there's any delayed contrast enhancement change. So in conclusion, an interesting paper, let's leave it there. Okay. Thank you. The next paper and I cannot, I cannot have any bias into it because I was the PI of the paper. And in fact, it's the anticoagulants strategies in non critically ill patients hospitalized with COVID-19, a randomized clinical trial. Well, you know, the the traumatic phenomenon in the micro circulation in the large circulation has been one of the issues uh in COVID. And so we did some first retrospective studies in which we really look at anti coagulation, therapeutic anti coagulation, which was of some benefit in the retrospective studies that we did on Mount Sinai. But this led to the prospective study that I'm going to be presenting here. The so we sought to determine the safety and effectiveness of therapeutic dose of anti coagulation in non critical hospitalized patients with COVID. As I mentioned, the patients hospitalized with COVID 19 not requiring intensive care unit treatment were randomized to prophylactic dose of an ox A parent and therapeutic dose of an ox a parent or therapeutic dose of a pixel is interesting because this is one of the studies that we use an oral agent, a pixel on for the issue of COVID and Tom mcginnis City. The primary outcome was the 30 day composite of all cause mortality requirement for icu level of care, systemic embolism or ischemic stroke, assessing the combined therapeutic dose group compared with the prophylactic dose group. So we compare both therapeutic groups of of an ox a parent, an epic versus the prophylactic group of an ox a parent. This study was carried out between August of 2, uh 2020 in September of 2022, the patient is a large study in terms of 3398 non critical ill patients. Again, they were hospitalized with COVID were randomized to what I mentioned to the prophylactic dose of an apparent versus the two therapeutic dosages of Pixar and parent 76 centers participating in the study in 10 countries. The 30 day primary outcome a cure in 13 Percent of patients in the prophylactic dose and 11% of patients with the combined therapeutic dose. The results didn't reach a statistical significant. Then we have the secondary endpoint. One was all cause mortality, securing 7% of the patients treated with prophylactic dose of an ox opinion versus 4.9% of patients treated with therapeutic dose of anti coagulation. This was highly significant intubation was also highly significant 8% versus 6%. And so the combination of both and that is the intubation and then the other aspects that I mentioned. So I have to conclude that among non critically ill patients hospitalized with COVID 19, the 30 day primary composite outcome was not significantly reduced with therapeutic dose of anti coagulation. However, when we look at the issue of mortality and and and an intubation, the results were highly significant. So just of interest to say that in the United States, the study, the primary endpoint was superior than to India, which really the outcomes were very, very low. So this is one aspect that it is important to mention. The other aspect it is important to mention is that the patients who had lung disease with chest X ray with city A rds. Again, the results were superior in the primary endpoint with the use of anti coagulation. Anyway, this is open to discussion Pump. Let me ask you a question. Um Was there any relationship you know, over that period of time, there were changes in the, the prevalent COVID variant, have you looked at or do you, do you know if there were any differences, we know that the results are more significant in the first part of the study than in the second part of the study? And this is one of the issues that we kept going to meet. The number of patients that we want, that we wanted were more than 3000 and this delayed the study. And at the very end, we ended up with the second part in which the incident rate of events was decreased. So if we had started, I think much earlier, probably the results will be different. I agree with what you said. I think, you know, we certainly saw COVID early here in New Orleans in March of 20 and the uh throw metabolic complications were much worse. And I think many of these patients had micro pulmonary emboli that may not show up on A C T A or something like that. But I think that played a huge role in some of their outcomes. And so I think anti coagulation is important but just with the variation and the virus and international variations in care, I think it's difficult to extrapolate the data to whatever comes next. Well, I think it underscores also the importance of in the trial construction of the here where the actually the secondary endpoints ended up being probably more important than the composite, the composite endpoint in terms of analyzing the study. Um I think it also points out that in clinical practice so important for us to individualize the care of the patients. So if you have somebody who has has demonstrated lung involvement or prior lung disease, other increased risks for throttle, symbolic problems and balancing it with their their bleeding risk. At least we have some information now to help us make that decision a little bit better. There's a statistical point which I think is of interest and that is we look at the first event of the four composite endpoints and the first event was intubation which overshadow the mortality. So this is very important from the statistical point of view. If you, if you do the opposite, you say, well, the most important is mortality and you start from mortality and then you so, but these are things that, that are interesting. But anyway, I think the study is the largest study. And I think our conclusion is that this has to be individualized, as you mentioned, particularly in patients who present with lung problems. So they are at high risk but not necessarily go to an intensive care unit. The therapeutic approach, persist prophylactic approach. It's important this study had to be done in the sense that through much of COVID, um we were sort of flying by the seat of our pants with throwing anything and everything and um without randomized controlled data, this study had to be done. And um I'm glad that these results are published, investigator driven have to get the funds to do this study where industry was not involved at all. So we feel good about it. Thank you very much. So, let's now move into, I guess is um the other study? Oh yes. Is the Bio Bhaskar study? Very interesting. This is a study presented by Dr Dill Etti from the Rotterdam and his complete revascularization strategies in patients presenting with acute coronary syndrome and multi vessel coronary artery disease. It's an interesting topic. We all know that A large number of patients with acute coronary syndromes actually present with multi vessel disease. Certainly more than 50 in multiple studies have established the clinical benefit of complete coronary revascularization as compared with the exclusive re perfusion of the culprit lesion. The question has been about the timing, the optimal timing for the non culprit legion revascularization is actually remains unclear. So the primary objective of the bio vast trial was to investigate whether an immediate complete revascularization is not inferior to a stage, complete revascularization strategy. And the primary outcome is a composite of all cause mortality, myocardial infarction. Any unplanned ischemia driven revascularization and cerebrovascular events at one year post index procedure. Number of patients in this study, about 1500 culprit lesion was clear. So the other arteries were looked at and then here we come, the immediate complete revascularization during the index procedure was done in over 700 patients and was a stage approach with revascularization within six weeks. In the other over 700 patients, the composite primary endpoint, I repeat all cause mortality, myocardial infarction, any implanted in ischemic revascularization and cerebrovascular events at one year. Well, the results were actually interesting in terms of the primary end point. It was a superiority of doing the procedure at the time of the patient having revascularization of the culprit lesion, 7.5% versus 10%. The primary outcome in the group in which there was a staging approach. I don't think these results reached significance in superiority but certainly were very significant in non inferiority, which was the basis of the study actually was non inferiority. Mhm Then we have other aspects which is myocardial infarction. Actually, there was superiority here 2% in the group that was the procedure done at the time of the culprit lesion being involved in vs and 2% versus 5% in the staging. And actually, we reached the conclusions here is that in acute coronary syndrome, patients with multi vessel coronary artery disease, an immediate complete revascularization strategy was not inferior to stage complete revascularization for the composite primary outcome and was associated with lower rates of myocardial infarction at one year of follow up. I think it's an interesting study at the question is how you select the patients, you know, patients come with multi vessel disease. And then the question is if you're going to revascularization, non culprit lesion, what decisions are you talking about? So this is the question that I have. So what do you take from the study? Well, I think you bring up the point. I mean, obviously at the initial uh procedure, you also have to uh in addition to understanding the extent of their coronary disease is the complexity and what is going to be the additional sort of um concerns related to the extending the procedure in the in the setting of complex disease. These patients actually had complex disease, over 60% of them had A B or C lesions, B B or two C lesions. I I think one of the important issues here is really more of a resource issue. It has to do with shortening the overall length of time in the management of these patients uh lowering the total cost of their care by you know, avoiding a second hospitalization or procedure. Uh and also in the United States, the the interval time in this trial was about two weeks to the In the group where there was the stage procedure in the United States that would be over 30 days driven by, by the economics of reimbursement, which really emphasizes that patients have to wait 30 days until they have their second procedure. So I think there are some practical um insights into this trial in terms of the overall management of these patients. Um so I think it is an important study. Well, I think it's interesting, I don't think anyone would disagree with intervening on the culprit lesion, but to do it all at the same setting really makes it unrealistic to think there's going to be the opportunity for a heart team discussion about what to do with the other vessels, right? And there's no way to the search. It's not realistic to have the surgeon be there at 2 15 in the morning to look at the angiogram to make a plan for the other vessels. And so I think while in the short term, one year follow up there, maybe equipoise, I'm not sure that down the road, some of these patients wouldn't be better served with a staged approach so that there can be a hard team discussion about what to do with the other vessels. There's no discussion of bypass those who go on to surgical revascularization. In this the only other issue I think about in these patients, which they did bring up in the discussion is just the patients with maybe chronic kidney disease or the dye load of a complete revascularization. So I do think that there are some patients for whom staging may be more appropriate at that time. But certainly you can feel good about going ahead and doing it immediately other than as well. Your point with the team, I think Patrick brings up a great point. I guess it depends on then the the timing as we know in stem e patients. For example, it looks like in those patients if they have it during the same hospitalization, the treatment of the uh the secondary lesions may not necessarily need to be at the time of the uh culprit lesion. And that provides this opportunity for that conversation here. The average delay is two weeks. So this implies that they've, you know, gone home and, and perhaps missed that opportunity. So it's an issue of logistics, an issue of feasibility, an issue of the team being they're discussing what patients we should do this and that. And that's basically, but the study is interesting though at least it gives you both opportunities we have now to move into pulmonary hypertension. And there is one particular paper and pulmonary hypertension that I think is interesting is the so called stellar face T trial, a study of so to intercept in combination with background therapy for the treatment of pulmonary hypertension. And this was presented by the Doctor Marios Hopper from Germany. And it is a very interesting study. Certainly the results to me are fascinating. Well, first of all, what we are dealing at the molecular basis here, we are dealing first of all clinically patients with pulmonary arterial hypertension, which is a progressive disease as we know driven by pulmonary vascular remodeling. And they are talking about an imbalance into anti proliferated type of molecular basis versus pro proliferated. And we are talking about a drug today that I mentioned that this goes into the anti proliferated part. So it is like one part of the balance. This is the drug, the name is so to intercept is an active signaling inhibitor and is rebalancing this kind of balance going towards the anti proliferated effect of pathogenesis of primary pulmonary hypertension. Now this is the these are the details of the study. This terrorist study is a phase three randomized double blind placebo control multi center study, evaluate sort of intercept on top of a background therapy for pulmonary artery hypertension, you know in the filling receptor antagonist for dia stories, prostate cycling, et cetera. And in these patients efficacy safety data to treatment Uh 24 weeks was addressed in in so safety time of death, clinical worsening. So a number of clinical endpoints were part of the study. I have to say that I was impressed by the results here and I can go a number of variables that they look at in terms of endpoints. One of the variables was the six minute walk test and was significantly better in the group versus the placebo group. At least 40 more minutes, 40 more meters could be walking this six minute test. The palm a vascular resistance significantly decreased. Then the NT PRO BNP significantly decrease the functional class significantly decrease um and so forth. And then certainly all cause mortality and in progression of disease also decrease, uh you know, 26% versus 9% in terms of progression, 26% in the placebo group versus 9% in the group. So I have to say that I was very impressed by the results of the study. There is one issue here, bleeding events tell unchecked Asia trump aside, opinion increasing blood pressure, dizziness was certainly more significant in the group versus the placebo group. So here are the conclusions. This is a first Phase three trials with this truck. So to intercept improved the six minute walk distance, as I mentioned, reduced the risk of death and nonfatal clinical worsening events by 84%. And they say the drugs was generally well tolerated. I'm not entirely sure when you read the study, what you consider the toleration of the drug. But certainly the final statement is these results established the clinical utility of administering combination with a proof pulmonary hypertension, pulmonary artery hypertension therapies as a new treatment for pulmonary arterial hypertension. So, Pamela, what do you think about this. I was impressed but I decided effects. Let me a little bit down. I agree. I do think this is such an incredibly difficult group of patients to manage. You know, one of the things I was most interested in, you went through that list of all of the, all of the variables that were improved. The one, the one that was not improved was the measure of cognitive emotional assessment. And it's interesting because I do see with these patients, there is an overlying with, with a debilitating disease like that, there is an overlying emotional um it's very stressful to have that sort of an illness. And I was really amazed at all the clinical variables and, and uh and uh biomarker varia variables that improved, but the emotional cognitive did not. So that's very interesting as we've had the discussion about quality of life, etcetera. Patrick, not necessarily for primary ph patients, but for patients who get lung transplant in general, the average survival's about 5.2 years. That's terrible, I think. And so anything that can improve the outlook for these primary ph patients, I think it's great and it does come with some baggage admittedly. But versus lung transplantation, this looks pretty good. Well, I would agree with Patrick and Pam that this is a patient population where they are very ill they have and maybe they don't, they're not feeling well emotionally because they still have this hanging over their head. And it may be an ongoing concern. I think it is interesting, it sort of circles back to the discussion we had about try eliminating the importance of, you know, patient reported outcomes in terms of feeling better. Also was interested that the actually the increase in the six minute walk was fairly substantial, actually a lot greater than it was in the tri illuminate trial. So I think this is another arrow in the quiver hopefully for these very complicated patients. You know, it's interesting though, when you talk about the improvement in the six minute walk, which was significant and highly significant, It is impressive that when you calculate laid it out, it's measured just over 100 ft, which tells you how really debilitated these patients are of a statistically significant improvement is 130 or whatever feet that is, it tells you just how sick they are. Well, the results are impressive with a new drug. I never heard about it. It's fascinating. Well, there are three other studies we don't have time to discuss was one is important hypertension. You know, the use of massive tent and paddle a field they use, they are using combination in these patients. And now what they develop a suspect because adherence is always a problem. A polypill which is the combination of both and the drug did. Well, I have a number of questions about, about the study but certainly maybe in the future, we have a polypill in treating these patients with pulmonary arterial hypertension. Another study I think is interesting. It was a Phase two trial Within a normal PCS K nine inhibitor. And, and it's fascinating, it drops the cholesterol level as well as with the directed we inject is indeed very, very fascinating at least is in a phase two trial. And finally, I think it's interesting patients with hypertrophic cardiomyopathy. They can, they can do as much exercise as they want. Well, this is also interesting. Well, this is basically, um I would say a summary of what has been presented in this meeting. And maybe I will ask a question to each of you which trial or trials you think were interesting in this meeting as a final summary, Patrick, the trick. I think that's a big deal because those patients, when they're symptomatic, there's no good solutions. And if this trans catheter approach can provide at least palli ation if not improve survival. I think that's a big deal. Well, you know what I'm gonna say, the clear outcomes trial in my area, it really opens up additional doors for these really high risk, difficult to manage patients. Well, I would agree with Pam, I think from a day to day practical general cardiologist perspective, I would say that the clear outcome trial was really reaffirming of our LDL hypothesis and also gives us, you know, really something that we can offer patients who may not be taking a therapy that we know to be beneficial. Long term. I tend to agree with all of you. The true illuminate study. I think it is very important. And then the clear study, I think it's very practical on a drug that is already available that we can use every day. Well, look, thank you very much. You have done very well. The only thing is not too much controversy. I wanted to have more of a fight here, but it didn't come through were very agreeable. Yeah, anyway, thank you very much. And thanks to you, the audience who are here to at least to listen to us. And about this summary was an interesting meeting in terms of the number of subjects being approached. Most of the aspects in cardiovascular medicine were there. We didn't get into electrophysiology today. But anyway, I'd like to say it was a good meeting. You as president of the American College of Cardiology. You have to be congratulated. I mean, this is a biomarker that it is good. Uh And thank you very much to all of you being in the audience and thanks to the three of you to participate with your knowledge about this, uh the judgment of all these trials. Thank you all.
