Join Mount Sinai’s Valentín Fuster, MD, PhD, MACC, and a panel of experts for a discussion on the top trials from the ESC Congress 2024.
Chapters (Click to go to chapter start)
I am Valentine Foster from New York. And I'm very pleased today to review and the different presentations at the European Society of Cardiology Congress 2024 in this beautiful city of London. And I'm very pleased to have with me, four masters on different aspects in the cardiovascular field who will be able to discuss with me the most interesting papers presented in the Congress. So just to give a view, we are going to discuss nine papers if we have time. Uh one on cardiomyopathy, the uric story on amyloidosis two, an atrial fibrillation, oceanic A F uh A sun diction versus A pixel. The inhibit inhibitor of factor 11. Very exciting actually, epic coronary artery disease and doon in patients with atrial fibrillation and chronic coronary artery disease. So two papers for atrial fibrillation. Then we have two papers for myocardial infarction, the A beta Ys or Avis uh beta blockers interruption following myocardial infarction is good is bad we'll discuss and then the uh fire study complete versus culprit, a revascularization in patients with myocardial infarction. In this case with a functional assessment of the non cate lesions. Then in bubble, a heart disease notion three uh PC I in to patients who have coronary artery disease and aortic stenosis reshape HF again, uh moderate uh cardiac dysfunction in patients with functional micro regurgitation. Uh That is the approach with T er versus uh normal medical therapy. And then the uh patter patter patter horn, I'm sorry study, which is again moderate uh mitral regurgitation in patients with functional mitral regurgitation and moderate dysfunction of the left ventricle. In this case, is the use of uh T er versus surgical approach. And finally, a very controversial paper, uh semaglutide in patients with COVID-19. OK. So a lot of news about this last paper which will be worthwhile if we have time to discuss it. Well, let me now uh introduce my friends here, real experts in the field. Let me start in my left. Doctor James Janus, uh who is the Adolf hater professor of medicine at the Harvard Medical School Staff cardiologist, by the way, are very good cardiologist at the Massachusetts General Hospital and Chief Scientific Officer at the Bain Institute for Clinical Research in Boston. Then we have uh doctor Christine uh Doctor Christine Albert, uh professor and chair of the Department of Cardiology and the Lee and Harold couple of its distinguished chair in cardiology at Cedars Sinai Medical Center in Los Angeles. But the best title, she was a fellow when I was at the Mass General. That's the best title. And then we have uh an Anna Sonia Petronio, uh is chief of the Catheterization Laboratory, uh of the Cardiac an thoracic department of the University of Pisa in Italy, uh where she's uh working as interventional cardiologist. And finally, uh we have uh uh doctor Gray Dali, who's uh from uh Oslo consultant at the Department of Cardiac thoracic in vascular surgery there. And she's a director in Europe of the International Society for minimally invasive cardiothoracic surgery. Well, with these introductions, let's now go into the details. And let's begin with the first paper which is the paper from uh the Helius B study published in the New England Journal of Medicine. Uh The primary results are a phase three study of boric in patients with uh TT R amyloidosis with cardiomyopathy. Uh This paper was presented uh by Doctor Fontana from the University College in London. Well, what we can see the family, basically what it does. It prevents the deposition of amyloid fibril by actually blocking the tetramers to become monomers and to be deposited. Uh But here we have a new drug but Sudan is actually given subcutaneously in a RN A therapeutic inhibitor that is we are really blocking the synthesis of amyloid. Very exciting from a theoretical point of view. So let's now go into the studies, a randomized double blind outcomes study in att R amyloidosis patients with cardiomyopathy. The patients were receiving BRIC subcutaneously. Uh Q three months, 25 mg and placebo also every three months. The number of patients uh 655 and the patients underwent of course randomization, as I mentioned, um they have a wild type. 10% had was a variant of the TT R. These patients New York Heart Association classification were mostly in class 2 to 3. And uh but in terms of uh six minute walking uh test um equal or more than 100 and 50 m. I would call this moderate type of amyloidosis of uh cardiac amyloidosis. Primary end points, composite outcomes of all cause mortality and recurrent cardiovascular events. Uh follow up 33 to 36 months, uh interesting secondary end points. Uh the walking test, the six minute uh the uh cancer city cardiomyopathy score all cause mortality and uh changing in the New York Heart Association functional class uh very well designed study. And now let's go into something that is maybe a little bit complex because uh there is a group called combination group. Uh tides was used at the same time that uh but in patients, we were using tides before. And actually there is the group that is uh the monotherapy group which is on only uric. But let me uh let me say the 20% was a crossover. Uh So they needed the families. So I'm just mentioning this but it still is uh monotherapy. Well, uh these patients, the average age 76 years, uh they were 93% were male and actually the um the number of patients who had the variant of att R were about 10%. Ok. Let's now move into the results straightened primary end point, well, very significant in terms of the outcome of all cause mortality and recurrent cardiovascular events in the overall population and the monetary population uh favor with three run with uh uh uh a hazard ratio of about 70.70 0.6 in a significant P value. This is for the again primary end point and I repeat all cost mortality and recurrent cardiovascular events and then all the secondary end points that I mentioned before. The, the six minute walking, uh the Kansas City score all cause mortality, New York Heart Association class. They were all in favor of BRIC. Now going into some details, all cause mortality and recurring cardiovascular events, 28% reduction. Uh Then we have second in terms of uh all cause mortality alone, 36% reduction in favor of treatment. Uh The next one, we have uh oh greater benefits seen in patients with earlier disease in patients less than 75 years of age. Um 45 and 65% reduction respectively, all cause mortality in the earlier stages and then uh added benefit on top of TEM. So now comparing uh the drug alone uh with this, with the, the combination was a little bit better with the combination uh was a decrease in mortality 5%. And uh the overall result would decrease 5 6% well. And then we have here uh disease progression also in favor of the drug. And then we have uh anti pro NP predicting mortality. And uh finally, we have adverse events, the majority of adverse events were mild or moderate. So, here are the conclusions. Uh but, and achieve a statistical significant on the primary and all secondary endpoints reduce all cause mortality and recurrent cardiovascular events. In a contemporary population of att R cardiomyopathy. The results were consistent across all pre specified sub groups including patients on VR monotherapy and those on background, the families, acceptable safety and tolerability profiles as previously established. And if approved nutrition has the potential to become the standard of care for newly diagnosed patients and those progressing on stabilizing therapies. This is according to the authors of the study, Exciting James, what do you have to say? No, I I agree. It's exciting. Um patients with amyloidosis have gone from having no therapies a few years ago to now having several emerging possible choices. And so to summarize very briefly, the four major takeaways here are number one, they hit every end point that they examined. So from a clinical trial perspective, it could not have been better. Second. And I think really importantly, silencers previously required an intravenous infusion here. Now we have a subcutaneous administration every three months making it easier for patients. It was beneficial despite a background of titus that is interesting and important. Given the fact that we have emerging choices now coming including besides um other stabilizers, um uh CRISPR for gene editing as well as depletors to remove amyloid from the tissue. So understanding how these therapies work together will be important. And then lastly, and I think this is something I'm glad you pointed out the benefits are more noticeable early in disease, which really means that those of us that see these patients for valvular heart disease or arrhythmia really need to think about whether or not amyloid is present in order to get um, treatment on board at an earlier stage of disease. Thank you. Uh Ana, are you excited? Yes, I think I'm excited. I mean, in Valvo have disease you find, especially in the elderly, you find patients with this disease and now you have the opportunity to treat them. And I think that helps more the evolution of valve heart disease patients. I mean, you definitely, I suspect you're excited too, but this is much better than the families. I don't know. Do you? Well, it there isn't a head to head comparison. Um, but you do see the benefit over it. So you imagine that at least it's additive and, and you know, we use multiple medications for multiple disease process. So having two would be great in this study. No, it didn't participate. But uh I've been evaluating in the ethics committee and we are a bit, we were a bit concerned about the gene manipulation and if we are going to start it in younger patients, will they have any, will there be any adverse events? But we never know. So, but it's exciting. It's a new type of doing medication. So I think it's good. Ok, final question, James. Uh we discussed the families. I don't know, but certain subcontinent every three months is very appealing frankly. But the other question, could you, do you think when the drugs are available they can be used both at the same time? Yeah, that's that literally is the million dollar question. And it's, it's likely that there will be controversy about um coverage because these drugs are going to be expensive. And so understanding whether we will be able to use two drugs at once may be in part determined by the cost of the therapies. Well, thank you very much. It seems to me we are all in agreement. This is a good move in a very important study. Exactly two studies on atrial fibrillation. We all have been talking about factory 11 neutralization. Here we have a very interesting study. The oceanic KF study also published in the New England Journal of Medicine as in Deion, the factor 11 inhibitors versus apixaban in patients with atrial fibrillation. And this was presented uh by Doctor Patel and the first author of the paper is Doctor Pini from Duke. And I think it's very interesting uh we, we all know about directoral anticoagulants a little bit better than warfarin in many aspects in patients with atrial fibrillation. But still, we have a question of bleeding. So this is where this paper is quite pertinent. Factor 11 inhibition. Well, I think it's like a miracle. We are told that it blocks thrombosis, the intrinsic factors, but the extrinsic factors that protect us that is the clotting system. When there is damage of the artery, you really, you cover that. It doesn't prevent that. So very good for no bleeding and maybe a good antithrombotic. This is basically where all this started. Well, let's go into details. It was uh an original study. A phase two study, Pacific A F study. And basically it was a study looking at what is the right dose that will make this drug perhaps good competitor with the director of anti coagulants. Uh Inos was choose uh was chosen. Then here's the hypothesis. A su at 50 mg daily will be at least not inferior topix Aan for the prevention of a stro of systemic embolism. Then another hypothesis also power to determine if a seduction is superior to Apixaban for the reduction of measures be or measure bleeding. Well, this is the study is the large study worldwide. 18,000 patients follow up a two years and we have here the two agents, a induction 50 mg daily and I pick 7 5 mg or 2.5 mg twice daily monthly monitoring of adherence, etcetera, primary efficacy and point stocco systemic emboli as we mentioned, and the primary safety end point measure bleeding, primary net clinical benefit and point altogether. Well, let's see perhaps more details. Uh these patients with patients with atrial fibrillation, of course, with indication for indefinite treatment with an anticoagulant. Interesting that Chad's bask score was rather high, equal more than three in male or equal, more than four in female. Average age 73 years, 35% women and few patients, 18% have uh actually kidney disease. In kidney disease, we tend to use Apixaban at a lower dose. Um When we use a direct oral anticoagulant, everything went into the wrong direction. Interestingly, let's look at the ischemic events. Well, 1.3% in the section group versus 0.4% in the pixel group. Unexpected. Well, unexpected, not known. Let's put it in this way. What perhaps was unexpected was the bleeding rates which is slightly different but not much different. 0.2% versus 0.7% strokes, less than 0.1% 0.1%. So this is the business of the bleeding. What happened is the incidence of bleeding was low from the very beginning. So the hypothesis is a little bit of a of a problem when you talk about bleeding today. Well, let's continue conclusions. Interesting conclusions. Apixaban 50 millions once daily was inferior for prevention of a stroke and systemic embolism compared with Apixaban in patients with atrial fibrillation at high risk for a stroke. You saw the differences though the majority of patients had previously been treated with oral anticoagulants uh importance. This issue is observed rate of a stroke and systemic embolism on a pixel in this high risk population was lower than previously observed. So the results actually were not an appetizer and this is why uh in fact, the study was uh close before the total recruitment of patients, people were concerned with the original hypothesis. So anyway, let's, let's start with you. What, what do you think Christine about this study? Something that we have been dreaming in this factor 11, maybe we need a new dose. What do you think? Well, there's a couple of hypotheses, I mean, obviously there's no free lunch. You know, you try to reduce bleeding, it seems that every time we try to do that we increase the risk of stroke. And, and so that is one of the issues. Um I think it was a good study and it was an important result. We had to know this. Um you know, there are people have brought up hypotheses that a lot of that could be due to the fact that some of these patients were already on an oral anticoagulant. And so you have the withdrawal of the oral anticoagulant with the factor 11 and maybe it's not as effective as it would be in naive patients but that would be a hard trial to do. Um, so I think where it leaves us now is that this just is right now, not an alternative, I guess you could try different dosages, but it doesn't make me excited. Yeah. Well, as a certain, I would embrace if they could come up in a drug, uh, compare, uh, competing with Apixaban because if people come in for operations, uh, acute a sections or whatever, it's really, really uh a pain with the bleeding, but we need to operate the patient. So, um antidote or an alternative drug that really be, be appreciated. What is your prediction? And this is going to work? Factor 11, we have to do many more trials. Perhaps they will try different doses to see if there is a chance for this uh this drug. What do you make of it? Yeah. Well, you know, as doctor Albert said, you know, we've recreated the frequently seen, um, you know, trade off of bleeding and thrombosis, I think. And, um, you know, to the extent that anticoagulants are the number one cause of adverse drug reactions in the hospital. I it's clearly an effort that's needed to be made. The challenge here obviously is whether they have the right dose or if they can get to the correct level of antithrombotic efficacy without increasing bleeding. And at this point, we just simply don't know any more questions. Well, we'll just see what the left atrial appendage closure trials show um comparatively because some of that what you're talking about could be eliminated if it was as effective as. So, let's wait, let's wait. Let's wait. But disappointing, disappointing, disappointing, disappointing. There are other 11 inhibitors being examined. So hopefully, you know, maybe they'll hit the sweet spot. Well, let's now move into the second paper on atrial fibrillation. Uh is the so called um Epic C ad also published in the New England Journal of Medicine. Today, Edoxaban antithrombotic therapy for atrial fibrillation and stable coronary artery disease. Doctor Nam from South Korea presented this study. This is a study from South Korea. Well, we all know that we have patients with atrial fibrillation and coronary artery disease. What I would say in the PC story, uh what we know is uh dual therapy, uh anticoagulation for atrial fibrillation platelet division for uh the coronary artery disease. So, dual therapy uh following PCI, there is some uh documentation that perhaps using uh an anti coagulant and uh alone would be sufficient and there's some data on that. But today, we are talking about chronic coronary artery disease and there are two studies, one using warfarin and the other using Trox as monotherapy. That in fact, uh the studies were not completely uh was not completed. So I think the study presented today is an interesting one. And that is Edoxaban versus Edoxaban with antiplatelet aging in patients with atrial fibrillation and chronic coronary artery disease. So we don't have the answer to that. But I think it is an interesting question. The question is maybe the they uh this particular edoxaban is also preventing coronary events in terms of coronary disease. A site of working for the atrial fibrillation. Let's go into some details. This is a multi center open label adjudicator master uh mask randomized trial comparing ox and monotherapy with dual anti thrombotic therapy. Edoxaban plus a single antiplatelet agent. In patients with atrial fibrillation and a stable coronary artery disease. This is important define uh as coronary artery disease previously treated with this vascularization or manage uh or manage uh uh medically. Uh This uh in fact, I think this were excluded is not, I I don't know anyway, but let's let's move into the primary outcome. The per car was a composite of all uh death from any cause, myocardial infarction, stroke, systemic embolism and plan urgent revascularization and me bleeding or clinically relevant non mesial bleeding at 12 months. So it's a composite of all the aspects. There are 525 patients in the Edoxaban monotherapy group and 516 patients to the dual antithrombotic group at 18 sites in South Korea. 71% 71 years of was the average age of the patients. 22% were women. And here we have three aspects. First. What about the primary outcome outcome? Which is was all together, as I mentioned to you before. Uh this is 6.8% in the Adan group and 16% in the group with dual antithrombotic therapy. Uh Now the question is anti thrombo. Why, why this great difference? Well, was not in the chemic aspects. So ba basically was in the bleeding was measured bleeding in the group of patients treated with dual drugs, 14% versus those with monotherapy 4%. So really what we are talking is about bleeding here. So I I want to read the conclusions from the paper in the New England journal in patients with atrial fibrillation and stable Coronary artery disease, Edoxaban monotherapy led to a lower risk of composite of death from any cause, myocardial infarction, stroke, systemic embolism and planned urgent vascularization or measures bleeding or clinically relevant non mesial bleeding at 12 months, then dual antithrombotic therapy. Well, this is an interesting study uh uh from South Korea, maybe the clotting system, there is a little bit different, it's more predisposition for bleeding. But anyway, James, tell me what you think. Well, I think, you know, um studies like this are really important because they provide practical information for clinicians. The combination of oral anticoagulants and aspirin is something that is particularly common. Uh in the United States. Actually, the you know, the removal of aspirin has been something or lower doses of aspirin have been argued for for years. And yet we still use dual therapy commonly. Um I I struggle with trials that mix efficacy and safety end points. And so I was grateful that we were able to see that what drove the end point here is a reduction in meaningful bleeding. And so it's a useful finding. The question will be with such a low frequency of ischemic events, whether a longer follow up would begin to close the gap with a recurrent uh with recurrent ischemic episodes. Yeah, that's right. This was 12 months, just a year. It's not enough in my opinion. And any comments, well, I I would think that this trial, it is one of the many that have been tried in the balance between anticoagulation and double anti plateau therapy. I mean, it's years and years that we try to fix this problem for bleeding. It is a complex population has a lot of, you know, medical therapy, uh chronic coronary disease. So it's really a mixture of uh of situations, but it's quite an important trial. Yes. Uh Christine, this is uh simplicity. You remember, oral anti Coagulans work for coronary artery, but was very tedious approach. And so here we have an agent which is an anti coagulant and I'm not sure price works for both and it simplifies our lives. What do you think? No, I agree. And uh you know, uh with patients a lot of times I am taking off the antiplatelet at this point regardless. So this is a nice trial to sort of support that practice if there's any risk for bleeding often. I will be doing that. Ok, thank you. So, what do you think about this study? I think it's promising. Uh I was like uh studies that show that breathing can be reduced uh And it can be safe. Uh I have patients coming with the platelet and I put them on Warfarin and I'm a, I don't dare to take away the platelets because the, the cardiologist said, you know, you must not do it. Uh So, so I think this is promising, but I, I agree we need to have a longer follow up in the study was in South Korea. You know, there is an issue, more tendency to be etcetera. So we need, we need these two other regions. Anyway, it's an interesting study. And now uh I think this makes us to go into myocardial infarction. Very interesting. The bit of locker story. Well, anyway, they be uh YSS or a study also published in the New England Journal of Medicine. And the question was with beta blockers actually is an interesting one. First, which is not addressed in this paper is people, should everybody give beta blockers from the beginning? If the ejection fraction is normal, this is not address here. In fact, all patients with myocardial infarction actually were receiving beta blockers for at least six months. And then in one group, the beta blocker was stopped and then see what happens in a follow up. So let's go into into the details of the study, the historical benefit of treatment with beta blockers after a myocardial infarction is well known and this is the standard of care to the patients with myocardial infarction. Uh uh The, the question is for how long you should give beta blockers? And uh we already mentioned when the ejection fraction is normal, maybe we need to answer that question. But the question is if the patient comes with an MRI and is on beta blockers, when do we should interrupt the beta blocker? And in this case, is done at six months. But again, we need details. So the beta blocker interruption on patients with a history of myocardial infarction and preserve ejection fraction actually was more than 40% would be clinically safe and improve patients quality of life. This was the hypothesis. Uh but this was an academic multi center open label randomized non inferiority trial conducted at tw 49 sites in France. The number of patients were actually pretty large here. 37,000 stabilize patients post M I. Uh for six months, all had been on beta blockers and in one group, beta blocker was interrupted. So what about the primary end point and this is important death, myocardial infarction, stroke and hospitalization for cardiovascular reasons. I'm saying this because that's the key of the difference in the whole trial, not in terms of death, myocardial infarction or stroke, uh evaluation at the longest. Follow up. Uh one year, uh minimum five years maximum. The average follow up was actually three years. Patients were actually over age of 18 years. And uh and I already mentioned the left ventricle ejection fraction. So let me continue the 3% in absolute risk difference. This is the 80% power to test no inferiority. We'll talk about this in a moment. Best line characteristics, age 63 years as an average 82% were male and then 62% had ST elevation, myocardial infarction, but the rest was non ST elevation. And then the ejection fraction interestingly, uh the uh was 60% the average ejection fraction but 20% of patients had between 40 50%. Most of them was normal ejection fraction though. Well, the results were interesting, I would have said that no inferiority. I mean the hypothesis. But here's the story. Uh primary outcome interruption, 23.8% almost 24% continuation, 21%. So interesting. What is interesting when you look at all the components of this primary outcome, the real difference was hospitalization for cardiovascular reason, had nothing to do with mortality, stroke or anything else. I think this is important. And now some details when you look at death, myocardial infarction and stroke, 6.8%. 7.2%. No much difference uh that myocardial infarction, stroke and hospitalization for heart failure. Here you see some differences 7 to 8.4% quality of life. The same uh hospitalization I already mentioned in favor of the continuation. Well, the question here is blood pressure. Interestingly, if you look at uh was a difference in blood pressure between both groups. So in the group that was interrupted, the historic blood pressure increased by an average of 3.7 millimeters of mercury. The diastolic pressure 3.9. But perhaps to me, most troublesome is actually the primary end point in hypertensive patients was certainly in significant favor for the non discontinuation of the drug. So we should keep this in mind. So, so here's the story in this study did not demonstrate actually the safety or other ways of interrupting beta blockers in patients with myocardial infarction and preserve ejection fraction. But there are some problems actually in terms of blood pressure. So the studies in terms of non inferiority depends what the statistics you use. But perhaps there is an issue here or two issues. One, the results related to hospitalization for cardiovascular causes. And the other thing is uh is worrisome patients with hypertension. Well, anyway, what do you think Christine? Well, you have the question, we always talk about the questions. Yeah, you know, I um there is something about discontinuing beta blockers. It's always made me feel a little uncomfortable even though, you know, the data in the other trials does suggest that it's non inferior. And I think that this gives you a little concern I mean, again, you know, hospitalization for cardiovascular events may not be as hard a outcome, but that's also a predictor of outcome later on. So, um you know, II I think I'm not as sure that that's really a safe from that trial. Um If I have a patient who is myocardial infarction today and normal ejection infraction, I don't want to discuss if you give beta blockers or not because this is being tested. Actually, we have a study testing that. But the question is, would you interrupt if the patient is not hypertensive, depends on the other comorbidities. Uh And uh for instance, the the 24th organ of the body is the aorta. And uh if the, if the hypertension you can develop dissections, aneurysm and so on. So I I would, I I really like to give the patients beta blockers because of the aorta. We see a lot of patients with the aortic disease and they benefit from that. Well, you're talking with great judgment. I only will tell you the following in my experience. And I would like to ask James experience beta blockers have side effects. So it's not so simple. You give a beta block and see what and you, you use them too a lot. So what do you think about this study? And I think that makes you think that perhaps there is a possibility of tailoring the therapy for patients. I mean, if patients has an hypertensive patient then you have to care with beta blockers. If the patient has some issues, then you have the chance possibly to interrupt it. I think it's, it changes patient. You talking with judgment. It did. That's what it is. Change. I don't know. So what do you think? Tell me the patient comes with an M I there's normal ejection fraction. I'm not going to tell you if you give or you don't give beta blockers because we don't know. But what would you do at six months? Right. So, so this study provides, I think some useful insights. First of all, in with contemporary revascularization techniques, the risk for hard cardiovascular outcomes at least over a three year period is low, which is reassuring. But as you said, um events did happen and, and yet beta blockers have side effects. So how do we find our way through this? I tell my patients that if I'm going to discontinue any medication, we need to think about the their case in totality, including whether they're hypertensive have other comorbidities. A history of atrial fibrillation. Um heart failure obviously is a an important thing to consider um in the balance of things, it's all about risk and benefits. So if someone has well controlled blood pressure, um a lack of symptoms, normal ejection fraction, I will discontinue I do in my clinical practice, but we do it carefully and we monitor to make sure that for example, this four millimeter increase in blood pressure that's very significant in clinical trials um won't occur because then you're exposing the patient to risk Christine. Um You, you deal a lot with beta blockers. I have always been concerned about the side effects when you talk to patients, really, you, you grasp the importance of this. So I guess I would like to you to with your, the questions you have about this trial and what is your experience? Well, I do think that there are side effects um for sure. Uh And you do have to ask about them. Once you start the medication, you don't get them. Yeah. And then all of a sudden you hear about the fatigue and some of the other things. Um but, but, but often they are well tolerated. Um And again, I think the one area here is, what about that lower ejection fraction group? You know, that was a small component of the trial. Do we really have the power to know whether 40 to 50? It's ok. You know. Um So again, as the person trying to prevent sudden cardiac death, even though there wasn't a signal there, yy, you know that those patients are more at risk than patients who have preserved ejection fractures. Interesting when we developed the polypill, which actually came yesterday as, as class one in the European for patients with chronic coronary artery disease. In question, all hes when you develop polypill was impossible to have four agents together was the beta blocker was interfering with the aspirin. You know, when you give the pills together is an interference which is different than giving separately. And we had to not to give beta blockers. It was very difficult from the pharmacological point of view. So, but anyway, I think this is a, is an interesting study and certainly we'll continue to have questions about bit of locust, but I tend to agree. Judgment. I think it's all what you're talking about the way we should address today. This is the the first paper in my card faction, but this is a second paper. My cardio fortune, let me see is the fire paper. It was published in Jack. Actually, um the paper, the title is complete versus copy only revascularization in all the patients with myocardial infarction with or without ST segment elevation. Actually, this paper is uh from the group in Italy and uh Marta Coco I respect is the one who presented the paper. Well, let's go into into the issues and that is uh complete revascularization is the recommended strategy today in patients admitted to the hospital with ST segment myocardial infarction. But there are two issues. Uh one is non ST segment elevation, myocardial infarction. And the other issue is there is very little data whether you look at the non CPI lesions functionally and then you revascularize those who functionally uh dictate ischemia. And this is the paper is addressing this and, and I'm going to discuss the details. Well, this is a multi center Italian study. The study aimed to assess whether complete reversal compared with culprit, only revascularization was associated with the consistent outcomes in all the patients were more than 75 years with a sty or non stemi. Uh There was a physiologically guided uh for computer rascal organization which we will talk a little bit later because I'm a little worried here. Uh was a wishy washy uh was wider based uh hyperemic response or not hyperemic response. And then a geography based uh uh quantitative uh flow ratio. So it was not really an FFR done to uh very in a very strict manner. II, I just mentioned this. Well, the primary end point is death, myocardial infarction stroke or revascularization at one year. And I, I want to emphasize rev revised colation because that's where the difference comes from. Well, the primary end point occur in 21% of the semi patients randomized to culprit only uh like 21% but 16% in the sty patients of the complete group, complete vascularization hazard ratio, 0.75. And then the non sty patients 20% or 21% versus 15% in favor of doing both. Uh and then the um the secondary end points which is to dichotomies, all of these were all border lines. So the question here is the, what, what is the conclusion physiologically guided? Complete reversal organization a little bit question mark compared with culprit only reversal organization provide a consistent benefit across the whole spectrum of patients with myocardial infarction. And this is uh with a reasonable follow up actually of one year James, what would you say about this? Uh Do, do you think this adds anything to what we know? It, it adds a lot more conversation with our colleagues in the Cath lab. Certainly. Um This comes up so frequently when our patients are in the lab and, and we get the call that they have the culprit lesion has been fixed and yet they have other disease. And what should we do about it? I struggle with results from studies like this in part because the knowledge of presence of coronary disease immediately will lead to a change in subsequent management. And so interpreting end points that are driven by revascularization um makes it hard to know if this is really a, a finding that's um based in physiology or knowledge of the coronary anatomy itself. Great. I, I have a question here and that is, it depends on the timing here. The reversal organization was all done a T the SA ME time, but you may wait two or three weeks perhaps in having the SA ME results. Yeah, I think so. And then you can maybe uh reduce uh the use of uh rev uh PC I. And uh also you have to think of a medical therapy with the small disease. So I think it is a clever thing to, to stage it. Well, I think that uh uh thinking about complete revascularization, it can be even done a sort of a couple of days after the the main procedure. Uh especially if there are these patients are elderly patients. So uh probably it is not, it is different from a younger population. So this uh I think this trial makes me think a little bit is not so straightforward to me, at least in my experience. Thank you. So, one question is the timing when you do the other. But I don't know, Christine, I, I have a number of questions about this paper, but I'd like to know your opinion first. Well, I think that, you know, the power of the paper too, I mean, you know, the, the confidence intervals were really wide and, you know, because they did this sub stratified, no semi, non, semi, it kind of reduced the power in both the two groups. Um So, and I agree with Jim, what he was saying about, you know, once you know that there's a unfixed lesion and somebody has chest pain, you're so much more likely to bring that person to the Cath lab that it is kind of the bias is there to, to know whether that's us or the actual physiology. J final question is the, is the functional aspects if you're going to revascularize completely, are you going to look functionally speaking, which, which artist you are going to revascularize in the non copy. There's uh so many, again, so many studies with mixed results about the use of physiologic assessment to guide revascularization that um I, I think I'd probably de depend on my interventional cardiology colleagues to make that call. Um To me the the larger question as is with the case with a lot of the studies that we'll discuss today is how will I manage that patient medically if I choose not to revascularize? Because the use of optimal medical therapy for ischemic heart disease and for heart failure for that matter, other studies that we can discuss um you know, remains sub optimal in general practice and many patients with, with obstructive coronary disease do perfectly well on medical therapy. So it's, it's, it's a complex discussion though. Yeah, I tend to agree with you anyway, I, I think this is an issue that we, we face every day. And actually, I think all of you, what you are taking is a, is a lot of judgment uh to do that anyway. Um the results. However, I want to emphasize the the data was in favor but had to do with uh revascularization afterwards. So, all right, we have uh now we are entering into, I guess bowel or heart disease. Uh Yeah. The first paper is the notion three study which is the, let me see if this is the, the notion is that which is PC I in patients undergoing trans cat theoric valve implantation. So, these are patients with coronary artery disease and CV aortic stenosis. And the question is, do you do t alone or do you do tabor with vascularization? So, uh this is a question that uh I I is in the literature and so forth. In fact, it's interesting that coronary artery disease is approximately 50% of patients undergoing T I didn't know it was so high and 10 to 20% of patients today uh in the general population are being addressed both at the same time, 10 to 20%. Anyway, there is no clear answer and this is trying to, this is the paper today in uh that is presented in the New England Journal of Medicine was presented the other day. This is an international trial uh in the Nordic uh uh Baltic region. Uh The randomized uh 1 to 1 ratio patients with severe symptomatic aortic stenosis in at least one coronary arter stenosis with a flow reserve, uh fractional flow reserve of 0.8 or less or a dynamic or a diameter of stenosis of at least 90%. So this was properly done basically with significant coronary artery disease and there was a PC or to receive conservative treatment. Um The um the the patients in terms of the uh primary end points that from any cause myocardial infarction or urgent revascularization, uh and safety including uh bleeding events and the bleeding event is an interesting aspect that has a lot to do with the discussion here. Well, let's go. Let's go. Now into the details is a total of 455 patients uh underwent randomization 227 PC I group and 228 to the conservative treatment group. Uh median society of thoracic surgeons. A procedural risk of mortality score was actually at 3% at the medium follow up of two years. Measure adverse cardiac events was, was the primary end point occurring 26% in the PC I group and 36% in the conservative treatment group. And now bleeding, you have 28% events in the uh non PC A group uh in the PC A group, I'm sorry, and 20% in the conservative group. And uh so the conclusions are interesting because I don't, I don't, I don't agree with the conclusion. The first part, I agree. The second is omitted among patients with coronary artery disease who were undergoing tabor PC. I was associated with a lower risk of a composite debt from any cause myocardial infarction or urgent revascularization at the median follow up of two years, then conservative treatment. But when you look at the bleeding, you begin to be concerned because it's very significant. So I'd like to ask uh maybe uh you guy what your, what is your opinion about this study of doing both at the same time? It looks good on, on paper. But when you look at the bleeding, you begin to have concerns. I totally agree. And it, it tries to mimic surgery, doing both. We always do surgery. We, we, we have to wear about scoliosis. You see if we, if we, if we replace the valve. But here I was discussing also with the daughter and, uh, I, I think we should kind of personalize it in patients without angina. You should maybe leave the, leave the coronary obstruction alone and then take it later on if it's necessary if they develop angina. And I also think patients with the aortic stenosis, you cannot trust the F fr. OK. Thank you Christine. No, I think that um I, I agree with you about the bleeding and I think personalization is really important in this using judgment. I don't know that we can just all of a sudden start vascular everybody. I think that we, we need to understand more because at the beginning of Tay era, we used to, we copied the surgeons, surgeons do bypass and uh uh a VR and we did the same thing, but probably it's not so straightforward. We should need to sort of think about it before we already have four papers being discussed. Perhaps five in which the word from you is judgment and medical therapy, right? And that medical therapy, I, I completely agree this is um uh and, and, and equipoise as well because we're learning over the years how to manage patients with TVER and let we are revascularizing fewer and fewer patients now because we see that with good medical therapy after after valve replacement, they often don't have angina. Well, anyway, uh let's continue. I I is a number of papers being presented which are, are fine, but uh still judgment is the, is the, is the right word, isn't it? Well, let's see now. Um continuation with B or heart disease, they reshape HF two study. This is a study entitled Transcatheter Valve Repair in heart failure with moderate to severe micro regurgitation. I would say more in the moderate side. Uh Doctor Anker presented uh this paper is uh from Berlin Germany and uh and just uh I'd like to start talking about coop which is the trial we have uh in co op uh patients with uh secondary mitral regurgitation. Uh was a lower rate of hospitalization for heart failure but also a lower rate of death from any cause. I think this is important. Well, I don't want to touch into the micro uh French study. Uh but just to say that this study um was actually moderate in my view in terms of ejection fraction in micro regurgitation. Uh for example, the uh the mi regurgitation in terms of the volume was was rather low in the, in the, in terms of the artifice, effective artifice I think was 0.2. So it was rather moderate micro regurgitation. But let's go into some details. This is a randomized controlled trial involving patients with heart failure and moderate to severe functional micro regurgitation. From 30 sites in nine countries, the patients were assigned 1 to 1 to either trans catheter mitral valve repair and guideline recommended medical therapy versus medical therapy alone. The three primary end points were the rate of the composite of first or recurrent hospitalization for heart failure or cardiovascular death. During 24 months. The second, end point, the rate of the first or recurrent hospitalization for heart failure and the third is change in the cancer city scoring for heart failure. Number of patients, 505 505 underwent randomization. Not many patients, 250 were assigned to the device group and 255 in the control group at 24 months, 37 events per 100 patients in the device group. 58% in the so called control group with a P value of 0.002. The rate of first or recur hospitalization for heart failure was 26% events per 100 patients. Years in the device group were 46% in the control group. And then the the cancer city score increased by 21 points in the device group and eight points in the in the control group. The device specific safety events occur only 1.6% of the patients. Now uh the conclusions of this study are similar to the conclusions that we had in the co op study, except all cause mortality was not dropped. So, among patients with heart failure, with moderate to severe functional micro regurgitation, who received medical therapy, the addition of trans catheter mitral valve repair led to a lower rate of first to recurrent hospitalization for heart failure or cardiovascular death and a lower rate of first or recurrent hospitalization for heart failure at 24 months and better health status at 12 months than medical therapy alone. So at least what I can get from the study, it is very similar that the coop study, the number of patients is smaller and perhaps the patients have less significant disease. And this is why all cause mortality didn't drop James. What do you think? Did you learn something here? So I I would say that this study troubles me in a few ways. One is that it took 10 years to enroll a relatively small number. Second, the evolution of medical management for patients with heart failure um was dramatic during that period. And their conclusion that compared to medical therapy, clipping, the mitral valve um was uh advantageous in this unblinded study. Um neglects to point out that only 8% were receiving SGLT two inhibitors, 16% were receiving scuba valsartan and not over 90% receiving comprehensive medical therapy for heart failure. So the concern I have is they compared medical therapy in 2010 to MitraClip. Um And so, what we know is that comprehensive medical therapy, particularly with SECU Berl Valsartan, um excellent uh um uh application of SGLT two inhibitors beta blockers and Mras results in substantial reverse remodeling. We've shown a 50% reduction in the need for clipping of the mitral valve if a person receives that medical therapy. So I I would disagree with the conclusions of this study that they compared to adequate medical therapy. Actually, the number of patients was very small. That's the other problem. There's a risk. Yeah, and particularly in an unblinded study, the, the the potential for bias is pretty substantial. Any comment, Christine. No, I agree that those are all very good comments. I totally agree. I totally agree. Not convincing, not convincing. Well, I don't know if the next is convincing too. The Macon trial, uh transcatheter versus surgical mitral valve repair in patients with heart failure and secondary mitral regurgitation. Let me summarize uh very, basically, the paper is trying to say that uh mitral valve repair is better uh in terms of few end points. However, the degree of mitral regurgitation is significantly different. Obviously, after the T er versus the the versus the patients uh uh treated with surgery and the follow up is very short. So in my view and just presenting, I don't think you can and the patients had moderate disease too. I don't think we can say much about T er, being better when in fact, you're left with a degree of micro regurgitation there, which at one year may not be problematic, but long term can be problematic. What do you think? I say the same because here and the surgical group, I think it was like 72% that was repaired and you have to, to let it go a longer time before you can say the difference between uh tear and the and the surgery. And especially they say a tear has uh is uh successful if you do, if you have two plus regulation and we would never leave a patient with two plus regulation and surgery. So I think that if you wait for the results, if it longer time, it will be better. Well, I think that we have to remember that we are talking about functional micro regurgitation and uh putting a patient under surgery in function might a regurgitation. It is not the same thing uh with the primary Mr So I would be a little bit more caution. I, I think that it's been difficult to enroll these patients. Exactly for this reason because uh tr with this patient is more straightforward, safer in some way, they had a lot of complications with surgery. And so sometimes some patients, even if they have two plus left of regurgitation, they are functional, you have to treat the ventricle. And so probably they, they would be, they are better with judgment again. Again. Uh This is uh this is a great discussion from our interventional and cardiac surgery colleagues. I mean, it really does require judgment, discussion about safety and efficacy. Thank you. Let's go into this final paper which gave me a lot of headache but maybe not to you. Uh And uh this is the select trial, the effect of semaglutide on mortality and COVID-19 related deaths. I have to go back to the select paper that published in the New England Journal in 2023 which was uh semaglutide. Uh 2.5 mg reduced the primary end point of cardiovascular death, non fatal myocardial infarction and non fatal stroke. Um And these patients had pre existing cardiovascular disease overweight and they didn't have diabetes. And in addition, there was a lower uh a 19% lower rate of all cause death. Again, this is the use of semaglutide versus placebo. Well, we come into COVID-19 and I don't want to go too much into the details, but let's go into what has been news and that is the overall mortality. And I, I'd like to give you the figures. First of all, in this study was 17,000 patients, 13 had COVID, excuse me, 13,000 had no COVID and 4000 had COVID. And the question is the final results is a lot of data being presented and I read this paper four or five times. But the bottom line is that the overall mortality is 373.7% versus 4.9%. I say I am concerned because I don't know the patients who had COVID how the randomization work because it was not part of the randomization. And you are really is one point difference, 1% difference altogether. On top of it, we can go. The COVID people says we have an answer. Now we prolong life. But these patients were overweight and these patients, you know, uh had significant coronary artery disease. I presented to you my concerns, James, what do you have any concerns here? Is there nothing that G LP one receptor agonist can't do right. You know, um it's a post randomization variable. Uh so it's non randomized, right? And um although a large number of patients had COVID, um the, the question that I would have is how does one explain a 25% relative risk reduction on the basis of use of G LP one receptor agonist? And it may have to do with unmeasured variables. When people are on G LP one receptor agonists, they behave differently, they drink less alcohol, they are maybe more motivated to be active and exercise. I I simply don't know however how we can explain the result. Yes, Christine, I have a question about his comment. He said 25% relative reduction when in fact, is 1% absolute reduction. So I am just making this comment because he's right. But I am always concerned about relative reductions, don't you? Yeah, it's hard when you explain it to a patient to, you know, saying that you have a relative reduction versus absolute risk. Um But also, I mean, we know that obesity lead uh people who are obese are more likely to have death from COVID. So it's not entirely surprising um that this would happen. Um but would you want to put that into the entire population to prevent very difficult? Anyway, what do you think? And I remember last year when discussing the, we were discussing this, there was also uh I mentioned suicide but among the patients treated with the medication and they don't mention anything about that there, I think. Well, I'm a little bit worried that this drug does really everything and perhaps it's too much. Well, I'm glad you're worried all of you because I was worried, I was worried too. Well, this is excellent. Look, there are other studies, the sequoia uh and with hypertrophic cardiomyopathy and the use of a can uh senior study, the Guar to study the fine arts study uh with fine, but we don't have the time to go that. But I want to ask you, which is of all the studies presented today, which we end up with judgment in most of them anyway, which is the study in each of you that you feel most is going to change your practice or you are really looking at things differently. You James, uh, the Helios B study? Ok. You, I think that's the most impressive study as well that even me think that. Yes. So it seems to me that we can judge this meeting now. And I think, yeah, I think this was the study of the meeting and in all the other studies we really would. I was surprised about the as suction study versus a Pixar study didn't go in the direction that we wanted. But all of this is really judgment. All of the rest is really judgment. Well, look, I really appreciate this discussion. You are very good people. Uh There was no much controversy. This is the only war that I have. But anyway, it is very nice that you came here. And thank you very, very, very much. And thanks very much to the audience. I hope you enjoyed this discussion and looking forward to be with you again in the American Heart Association meeting in Chicago. Thank you.
