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No, yeah, I am parenting foster from new york and it is a pleasure again To have one hour discussion With four professors here about the breaking trials of this spiritual meeting. Is the meeting virtual exciting. Well we'll try to make the trials exciting to you and this is the plan that we have this morning or this afternoon or this evening for you. And at this place we are going to address as I mentioned, eight different trials. And we will start actually like session by session and we will start with session number one of this meeting and and I will discuss in a moment exactly the titles and so forth. But before I go any further, let me introduce my colleagues here very well known by you and dr lin Stevenson is director of the cardiomyopathy and heart failure program at the boundary Bill University Medical Center in Nashville Tennessee. We have doctor and Curtis who is the chair of the Department of Medicine at the University of Buffalo new york. We have dr wayne, Bachelor director of interventional cardiology, interventional cardiology research at the end of a hospital in Falls church Virginia. And finally obviously we need a surgeon here and here. We have it very well known to all of you has been with us many times before. Dr Michael max, Medical Director of cardiothoracic Surgery for the Baylor is caught in white shelf and the chairman of the ah Bs. W. The fire hospital in Plain Research center in texas. Well, thank you very much for uh you've joining me in these discussions and I hope we have fun. And now we are going to go into the titles of the presentations. The ones they thought were interesting. On the first session we'll discuss paradise in my the role of barney in in pasta, my low ejection fraction, the layer street trial or left atrial appendage disclosure by the surgeon to prevent from embolism. And then we'll go into the atlantic. Very interesting antique robotic therapy in cover where we are, where we are going. So let's begin with the first study uh that these um he studies the Paradise in my trial or the title actually is and you're tense intercept on the loose in division of army following acute myocardial infarction. Primary results of the Paradise in my trial. This was presented by DR mark effort from the Brigham and Women's hospital in boston. Well, let me introduce the situation and uh and you know very well in the 1990s, ace inhibitors came In, patients with heart failure. Great results, decreased mortality. In the early 2000s receptive blocker um drugs came like both starting and so forth. Great results also in heart failure in terms even immortality. And then more recently we have developed certain secure vitriol combination of Army. Also great results in patients with heart failure. Well, but there is no much actually on patients during the early stages of myocardial fortune. And this is actually the study that we are going to be discussing in the next few minutes. And this this paradise in my study. This is a study actually of 6000 patients Uh with them. I and just let me say that 76 were stemming in 24 were known as to me. And these 6000 patients came actually from 41 countries. And uh and basically these were patients with an acute myocardial infarction within the first seven days With an ejection fraction equal or less than 40 and or pulmonary congestion. These patients, 6000, about 6000 were randomized into shock. Could be true about certain. Uh, twice a day in ramie pio. Actually, the The security of bar certain was 97 103 mg, respectively, remit real Twice Daily five mg. So here we have the combination. This is running pill. Now, the follow up was actually close to two years is not a long follow up. And actually the primary endpoint is combination of cardiovascular death, heart failure, hospitalization, an outpatient development of heart failure. All right. And uh, and here we are. If you really look at the primary outpoint outcome. I'm sorry. As I mentioned with cardiovascular that first heart failure, hospitalization or outpatient heart failure. The results were very close with both groups. Seven points per 100 station years in the wrong people. 6.700 patient years in the security about certain. But then there is a a departure here. And what about what has been done in other trials, Not only to look at the first event, but the first event and recurrent event. And by doing that, then the results becomes significant in favor of the security above certain. So Islamic real. There were 10.1 events per 100 patient years. And then the security was certain 8.4 per 100 patient years. So that's basically a difference with the other results. Then there are the side effects were actually very similar between both groups. And I'd like just to move into the conclusions and rule open this for discussion and the conclusions are as follows, in a big, grossly managed enhance this acute myocardial infarction population. Compared to active therapy with remedial security will circle did not result in a significant lower rate of cardiovascular death, heart failure, hospitalization or outpatient heart failure requiring treatment Number two. Please specify observations of reductions in the total or recurrent events support incremental clinical benefits of security, Lindvall, certain and finally, the safety and cholera bility of both arms were actually comparable. So here we have primary endpoint in which really it didn't work. And then we do what is now being done in a number of trials is to look at the first event and then subsequent events. And here the results became significant. Well, let me uh, go now to just for some questions that I have for you and I like to see your views lin. What do you think about this trial? So, I think the paradise trial basically demonstrates for us how incredibly effective ace inhibitors are. They really changed everything. And on top of that, it would be hard to show a benefit. And I don't think we really showed one here. Even if we can re adjust the endpoints, there really just about one event per 100 that's prevented. And I see this as a largely negative trial. There may be subsets that might benefit, but don't see this as an imperative to use security val certain instead of an ace inhibitor after an Emmy. Except the follow up was short. And what do you think? Uh Yeah, I agree with Lynn. I think what we've seen is just how incredibly effective the drugs that we already have our if you did this Arnie study against Placebo, you know, you see a huge benefit in terms of using it, but now that we've got these drugs that have been around for so long, it's hard to see much to see much of a difference. Uh And so yeah, I agree with Lynn and it doesn't really push you towards using the combination. You know, if if the cost was the same in patients and there's maybe a little bit of a signal of a benefit then maybe you switch over. But it's not a compelling argument to change course now. Thank you. Wait. I also broken. I also think it's really important to recognize that the post and my population is very heterogeneous and they've just used Philip class but there are patients who are high pop refused patients who are asymptomatic with a lower E. F. I think we need to look at these populations individually and not try to come up with one therapy for everybody. Thank you wayne. Yeah. I think the other message in this is how important is to stick to the primary endpoint in evaluating clinical trials. I mean we can do a lot of secondary analyses and slice and dice data and look at it. I think dr Stevenson's point was very important when I'm looking at second area or other endpoints besides the primary, I'm looking at the magnitude of difference as well as the statistical significance. And as Dr Stevenson pointed out, the magnitude difference was very modest. So as dr Curtis has pointed out when you have an inexpensive drug that works that's generic, this in my opinion is not enough to necessarily supplant with that standard. Thank you wayne. Uh Michael. What do you get from here? I've got nothing further to add to what the other three have have said, I totally agree with. Okay, well thank you very much. Then let's move into the second one. The second one is really exciting. Uh is the layers of study, Little Street study, which means left atrial appendage occlusion study. He was presented by Dr Richard with Look, a professor of Surgery at McMaster University. And let's go into some background into this. Um So left atrial appendage occlusion has been festive hypothesis that can prevent a stroke in nature of population. And this is I don't think it's hypothesis is the reality. Uh But by based on a number of uh more recent studies, but we don't talk about surgery here. We are talking about the surgical approach and uh and the other decided to use surgical closure um uh the left total appendix and trying to look at whether or not this led to a decrease in ischemic stroke or systemic Campbell. I well, with this in mind this is the study actually, it was the largest study 27 countries participated And there were 5000 patients. And these patients actually were randomized is all underwent surgery and we'll talk about this in a moment. But they were randomized on occlusion. There's no occlusion and this was ah by the different techniques available to the surgeons to perform such procedure. What is interesting is when we talk about surgery, what we are talking about? Well, 20 of the patients actually have coverage and about 65 of the patients get about procedure, Not necessarily might. over 35 microns were 35 percent were aortic. So is all kinds of surgery. But what patients got into this study, this is very important because these patients are speak frankly. In other words, for example, 50 of car failure was in about 57 of this patient And then permanent atrial fibrillation, 31 in a church pastor Of an average of 4.2 was present also in a significant number of patients. So I think the question that we are dealing here is with a surgical approach on patients who undergo any type of cardiac surgery, who I believe at least are, you know, um, I would say are not trivial from the point of view of the disease, uh that they have are sick patients. Well, I go into the results now. The follow up was 40 years. There is a good follower and and the ischemic stroke or systemic Campbell. I must go system was ischemic stroke. Ah We have ah An incident of 4.8 in the group treated surgically Best of seven in the group treated that was not treated And then we go into secondary outcomes. Well, in terms of mortality was the same 22%. In both groups, we talked about the four year of follow up and so with the data presented, I think we we have a very good feeling what happened here. The surgical closure to reduce ischemic stroke, I would say relatively by 32%. And these patients actually, most of them were treated with anti coagulation 80%. So we have a situation is quite fascinating to me. And that is I have two patients today here that are going to be operated. One is a patient following at pathology follow. It needs something to be done in the left side of the heart as well as on the right side. And another is uh, is a micro patient requires a repair. This is this morning. And uh, and the question is both patients were very sick actually, not very sick, but what I tell my surgeons what to do based on this style. So Michael, tell us, what is you thinking? So, first of all dr foster this has been a quandary or a question without significant evidence uh, that has existed in cardiac surgery for for decades. And this is a strong evidence based that begins to answer the question, cause surgeons really haven't known what to do and referring physicians haven't known what to what discussion to have with their surgeon. I think on balance, this does say that in patients undergoing cardiac surgery with a chads, vast score of two or greater that you should air on the side of including the left atrial appendage. Now, this is not one size fits all as you've alluded to. There's a lot of different types of surgery that was done here. Uh, and it did uh, subgroup analysis. It did seem to be beneficial in all types of patients, including valvular and non valvular atrial fibrillation. Um, now there is the possibility of actually hurting patients, although there was no safety signal in this. So who shouldn't you do it in perhaps elderly patients with friable uh left atrial uh appendages, patients that are re operative procedures, patients that are done through a minimally invasive approach. And although there's concerns of of additional heart failure with ligation of the left atrial appendage, which is a rich source of A. N. P. Uh there was no signal of benefit here, but I still would be cautious in those patients is a change in paradigm is indeed otherwise, that this is a trial that has the potential to clearly significantly impact and change clinical practice. Yes, thank you. Well, yeah, I want to congratulate dr Whitlock and co investigators for for carrying out this study. This was a huge study, 105 centers, 27 countries and uh to follow up dr max comments, I think it does start to shift the needle. Um you know, there was a 32% relative risk production Trends for stroke translating into an absolute risk reduction of 2.2. So that's the number needed to treat a 45 patients to save a stroke. And if you're in there anyway, and from what I gather, this doesn't seem to require a lot of extra complexity, then it does start to make sense. I thought there was some interesting observations here. One, most of the benefit started to accrue after 30 days. That's what you would expect for something like a stroke in the future. But the curves looked like they continue to separate over time, suggesting the durability of effect here. Which is an important observation because some of these left atrial appendage, surgical closure procedures don't historically have not always lasted in terms of maintaining complete closure. There are a whole host of techniques used and the I want to congratulate them for also blinding the investigators and the research team. But there are a whole host of techniques used and I'm not as familiar with all the different techniques, but it'll be interesting to see over time if there's any sort of signal of one particular left atrial appendage closure technique perhaps showing a better promise than others. So I think in summary this does start to shift the needle and I think in patients who are at increased risk of stroke Again, Chad's fast two or greater. I think this does make sense if the surgeons feel if they can do it safely, thank you on. Yeah. One of one of things I noticed in the data that they showed is that they have, you know, there's still a fair subset of patients who aren't anti coagulated and follow up and these are high risk patients who have no natural fibrillation. So three years in the two groups, there was 75 and 78%. I'm curious about what where the strokes were. And if they tended to be concentrated among the patients who didn't have continued any coagulation, this wasn't available for this presentation now. But I hope that data comes out uh you know, as they get this uh published. But you know, because I think the concern I would have is you don't want people at this point to think that you can do the collusion of the left atrial appendage and then everything is fine and you don't need any coagulation. It should be emphasised that these patients remained on anti coagulation. Yet there was still a good benefits. Scene, Good point, son, when? Yes, I agree. I think this clearly shows the benefit and what a tour de force to get it done. I don't think we've answered the question about whether this might worsen clinical heart failure. Half the patients in this trial had a history of heart failure. And yet at three years the heart failure, hospitalization rate was seven impossible. So I don't think they got all the events that we would expect to see in this population. And so I think it remains an open question of whether there is an increased risk of heart failure events in some of the people who most need their natural peptides. Well uh certainly very interesting study. I think it will change practice but many questions to be answered. And ah and uh I think uh I think it's one of the most interesting actually presentations in this meeting. But let's move now into another presentation. And it's important. What do we do with stubborn wayne? I'm not asking the question yet. But what do we do with copper and all these anti prom biotics that are around You know? Let's go into the atlantic study. Okay. The atlantic study or so called antique robotic strategy toward all cardiovascular neurological ischemic and city etcetera etcetera. In the tower patients this was presented by dr jane Philip collette from from paris and I'd like to go into some background I think is important. And that is what do we do today? Let's start there. And you know there are two approaches. The patients who do not need anti coagulation for one reason or another and then we use play great innovation alone of patients who need anti coagulation and we use anti problems. Now here's the trick was one group or another. Let's randomize either pregnant innovation or anti coagulation with actually in this case with a picture of an and this was actually the question that was being presented interestingly. There's a previous study I think was the Galileo study in which the Baroque Stephen was used and the results were not actually quite good. But let's let's now ignore those. And let's go into the study If the objective was to demonstrate superiority of a picture and five million twice daily compared to standard of care. I already mentioned. Some are treated with anti platelets, some are treated with anticoagulants. And certainly a pick someone was actually um um Look uh this was the anti coagulation in one vs. Place with inhibitors in another. We are talking about the European multi century study 1500 patients after successful tower. And and I already said exactly how this was divided. I mean a group of patients at antique wagons versus a pick 75 million spice daily and the other was a pixel and versus platelet innovation. Different kinds of political innovation. What about the primary endpoint is a composite of many aspects actually. And my death stroke, systemic ambala intra cardiac bio prosthetic rhombus And measure believing over a period of one year. I just like to emphasize that one of the aspects was the identification of thrown by in the in the valve and they use city an echo. I think this is important. And in order to say the patient has a problem in the valve. It should be visible either with transparency take or for the city And should be a transfer prosthetic gradient of 10 20. Now go into details now order reducing reflect mobility. This has been pretty standard on the definition of crumbles in this by a prosthetic valves. Although we frankly we don't know if this is the way to do it. But anyway this was the study and now I'm going to be presenting the results. What was found first? The group of on anticoagulants. This is a group in which anti equivalents were compared with a picture of an Results. Primary outcome. As I mentioned exactly the same. 21.9 events. 21 9 events in the other group. I just want to be Sure of one issue is one year of power as I mentioned. 2nd what about bleeding Exactly the same. About 25%. Both. What about Trumbo's exactly the same? 0.9% 1.3%. This is about the group with anti coagulation pursues a pixel and now comes the second group. Political innovation or no need for anticoagulants versus a picture one. What about the primary outcome with 16 or 17 in their pick? 7 19 in the place with innovation group. What about breathing the same? 21%. Both. What about both from bosses? Interesting. 1.1 In the group treated with a pixel one, this is 6.1 in the group treated. Uh You know, we've played with innovation. So in conclusion, uh we have a situation here. The topics of an after Tabard procedure does not appear to be superior to standard care With anti coagulation in one group or with political innovation in another group, the safety is the same. However, subclinical vault from bosses is decreased in their picture and group. I don't know exactly what this means. And I suspect these patients have to be followed for a long period of time to know what you see in the valve has clinical significance. But when you deal with this all the time, tell me what is your reaction to this study? Did you learn something? Well? I learned something. But unfortunately, it opens up even more questions, as do some of these trials that have these sort of heterogeneous results on I think again, being a clinical trial of purists, this was a negative study. Um, it did not meet the primary endpoint, but there were some interesting signals clearly from the secondary endpoint analyses. I think first of all, the first comment is this is an extremely confusing and difficult arena in which to sort of make decisions. We we have in some cases, advocates of single anti platelet therapy after Tavern, dual anti platelet therapy is currently sort of the existing standard. And then of course, with patients who might have indications for anti coagulation, it gets even more complicated. So I think what the take home message for me is um, number one, uh, this is not supplant other prior gold standards for addressing anti thrombosis therapy after tavern. We're still confused as to what the gold standard should be, frankly. And I'll be curious to see what Dr mack has to say about that. But I think that number two, it was a safe Approach. There were, you know, there's no safety signal with using a mix of an in this manner and that's reassuring. And then finally, there were pretty dramatic reductions in bio prosthetic thrombosis of 77 relative risk reduction. So my take home messages um, and also in DVD of reduction. So my take home message and in patients in whom you're worried about bio prosthetic thrombosis or you perhaps have halt or some other indicators of concern. A trial of a pixel band seems to be safe and might be effective in those scenarios, but I don't think it supplants our current approach, which is already somewhat confusing, heterogeneous and unfortunately this doesn't move us anywhere forward in that regard. Michael. So uh, I agree with everything that uh Wayne has said and I would add in addition that we know from other trials that when you do surveillance screening for valve thrombosis, which is the reason Dana Quigley, these patients, that it occurs in anywhere from 25 to 30 of patients undergoing tavern. Secondly, we know that it is not associated with acute clinical events. And thirdly, from the evidence that we know there's no evidence that anything more than aspirin is beneficial in these patients. And we do know as you've mentioned dr Fuster that the Galileo trial was negative for rev Arax Urban. Uh and also there was a safety signal. So what we learn here is that there is no benefit to a picks ban over standard of care therapy. Whether you're on oral have an indication for oral anti coagulation or not ahead of time. But I do have some concerns about this study. You know the first of all, There were eight components to the composite primary endpoint which is the most I have heard in a trial and it combines an imaging component with clinical outcomes. And as we learned that the presentation uh imaging data was either absent or in a valuable in half of the patients. Uh so I don't think, I think that is a significant concern. And secondly, we've seen that the incidents of valve thrombosis found in this is between one and six based upon whether you're on a pixel ban or not, which is much much lower in other studies. So I think the conclusion of this is that there is no demonstration of benefit of a pixie ban. But I do have some concerns about the design and conduct of the study. Thank you Lynn comments. Uh No, I I've learned a lot from this. I do think it's important to recognize that a minority of patients were in the requiring anti coagulation section. So this is really largely based on the patients who did not have other indications for Orlando coagulation. Thank you on. Yeah, I think there's one positive spin I can put on this. I may agree with the comments that have been made so far. But you know when I have a patient who has already been established on any coagulation because they need it for atrial fibrillation. I don't want to be stuck looking at a patient like this and saying, jeez we should take them off and put them on platelet therapy or leave them the way they are. What this tells me is that if I had a patient who is already taking a picture of their for example, I don't do any worse keeping them on it. So the patients who have atrial fibrillation just traded with the pixel bands the way it looks to me and for the ones who don't have a need for any coagulation stick with the anti platelet therapy. Yeah, I was going to make the same common A pick someone is not so bad. After the river rocks haven't studied. I was very low in Knox in this, but at least in this study, Michael pick someone. It doesn't do so bad. So if the patient is the native population, let's continue. All right, thank you very much. We're going to uh to look at session # two now and there is a paper that I think is it's interesting uh is not earthshaking but certainly is bringing again into the discussion the possibility River rocks even low dose and aspirin in patients with that robotic disease. And the study that we're talking about is the boy chur ph d trial Or total ischemic event reduction with river rock seven after peripheral arterial revascularization. And this study was presented by dr the stupid both stocks from the University of mine and I'd like just to to present it because it's an interesting new approach to wanted robotic therapy that may be has some future. Well, there there are two aspects here. First is the original boys, your party study demonstrated that at three years, approximately 20% of patients undergoing low extremity revascularization. As we talk about today. The first advertisement or cardiovascular event despite of treatment with us for him was an statins and clopidogrel if necessary. uh it was 20 as I say, decrease uh or demonstrated an increase in events Which was significant of these patients. 20%. This was at three years. The additional river rocks. And in the original study, 2.5 mg daily or twice daily plus aspirin Actually reduce these incidents that they mentioned by approximately 15%. What is presented today? Is that the same we discussed before? What about the total number of events that take place over a period of three years rather than as it was done before the first event. And this is basically the approach that is being taken in the study. And now I will be presenting the basic data. So um This uh in this boy Jerry study which actually entail about near near 7000 patients actually was randomized peripheral arterial disease patients undergoing, you know, surgery, the lower extremity. And uh and they were randomized into river rocks around 2.5 mg twice daily plus aspirin, business, aspirin alone. And the primary endpoint in the original study was actually was the first event in terms of acute ischemia major amputation of a vascular cause myocardial infarction, ischemic stroke or cardiovascular death. What is new this time is the same story. But the current analysis involves all events first in subsequent and in addition vascular events, including peripheral revascularization and being a strong symbolism. So results. What we have here is that river rocks even uh together with us being reduced total primary endpoints With an h r of 0.86 compared with us being alone. And and also decrease the total basketball events. uh they say it's an estimated 4.4 primary until .4 vascular events per 100 participants were avoided, Which require oxygen over three years. 4.4 And 12.5. So in conclusion, and symptomatic peripheral arterial disease patients undergoing a lower extremity revascularization, you should have a say total event burden Uh these patients. And it appears that reference seven plus aspirin is efficacious. The department tries to make is that the number of studies now using this regime in native disease and disease after intervention, which is river rocks and very low those plus aspirin. So, I wanted to at least get depending from new people. Uh maybe wayne. You can you can take this one too since you're because of the intervention last. Yeah. Thanks Dr Foster. So again, not and out of the ballpark home run here. So number one ph. D. And vascular disease is a significant predictor of cardiovascular events. And I think this study really highlights that these event rates were quite substantial when you start calling them overtime. Number two, a driver of the outcome is going to be a vascular event in this patient population. So that's an important observation as well. One of the strongest relationships here between the outcome was whether patients had recurrent vascular events needed more interventions. Number three. There is a modest reduction obviously in uh the use of associated use of Career rocks haven't uh in this patient population. We've seen that before, but we're also seeing that this was associated with an increase in bleeding. So I think that when one looks at this, you have to sort of counterbalance efficacy with safety and then also factor and cost. Right now, River Rock Saban is significantly more costly than the standard of therapy. So, you know, I'm not I don't do a lot of peripheral interventions anymore. But if this was a patient that I was seeing, I would really have to look at the patient's risk of bleeding versus thrombosis. Uh look at the insurance plan. I hate to say it. But you know, we're asking these patients to take sometimes 10 medications. They're going to be on numerous medications. And if the if the pocketbook could only afford one other one, I would have questioned whether or not another class of medication would be perhaps considered. So I think I think it's a soft win, but it's it's not a game changer in my practice because because of the bleeding concerns and the cost and going about bleeding. And I agree way and this is the main concern. You know, the team, the measure breathing will increased by By 43%. The group that was treated with a pixel and in the with the combination with with the drugs, the combination of Little Rocks of an aspirin. It was 62 events in the hopes of an aspirin. And this was 44 events with us being alone. So I think it's an important point where wayne is talking about. And what do you think about do we? I think we have to be very careful with bleeding. This is a new regime that is being used now in many aspects of vascular medicine. But I like to your opinion. No, that's true. Uh, the effect of the river rocks, if it does seem to be durable. So when you look at the curves and as they go out, it's, you know, it's not that there's an early effect and then it sort of dissipates. So that would argue for continuing to use the drug. But the fact the expense of it is a point well taken. So, um, yeah, you know, it could be factors like the complexity of the revascularization. His way was saying, you've got to look at the whole picture. What's the patient's risk of bleeding? Was the patient's risk of having probiotic events. And, you know, is this a redo peripheral vascular intervention that was difficult or one that was maybe not so much. And then maybe you make the decision that way. But certainly this does not tell me that every single patient should be put on River Rocks, Iban. Thank you. Thank you very much lean. I think this is another example just as dr Masters said, where even though we can't rely on subgroups, we have to recognize that there are different patient populations with different risks of vascular events and bleeding, and we have to balance those for an individual patient in addition to the cost of the medication as well as the cost of bleeding. Sure, Michael, I agree with the other comments that this is not one size fits all by any means. And if you look at the potential benefits modest at best, it was kind of equally divided between uh scheme IQ events in the periphery versus systemic events in patients with uh peripheral vascular disease that are prone to stroke my et cetera. And if you just look at the patients with acute limb ischemia, amputation, acute revascularization, there is a mild benefit but not dramatic. So I agree exactly with what ANn said that uh if you're going to treat patients with River Rock Saban, it would be in those patients who are at highest risk for subsequent ischemic events in the extremity. And those are uh re operative procedures, extremely poor peripheral runoff et cetera. Okay, thank you very much. Let me go into ah Session # four, interesting. Uh We have uh a first paper we're talking about the H. D. F. P. Inhibitors in diabetic and non diabetic patients with heart failure with renal failure. But here in this particular paper they tried to compare I don't know if it is apples with oranges but basically it's a comparison of what is in the literature with TLT too inhibitors with. Now with the use of so to gryphus in which is Is an inhibitor of two and also a virtual one inhibitor. So uh He's a little bit of a comparison in the literature and and and frankly in time to summarize this I will do the best they can. But they wrote here five points. So you follow 1-5 in it you will get a feeling that look what this is all about. Well the first point is uh if we go back to the S. G. L. T. To inhibit as you know, can agree focusing and refocusing and paige refusing and so forth showed that improving cardiac and cardio renal outcomes in patients with or without diabetes and and uh and in some with heart failure and others with chronic kidney disease. We all know this. But now comes this drug, the Sota Gryphus in which is an SDLP two inhibitor and it's also an S GLP one inhibitor. And this leads to my second point. What is the difference? Well, as you know, the GFT two is in that receptor is is certainly in the urinary tract and prevents the absorption of uh of actually, well, it worked into the glucose transport. Whether the city of Taiwan is in the glucose transport on the small intestine, there are differences. Now what is G. O. D. One makes the difference here because what the papers tried to say is that the sorta gryphus in may be superior to the other because it affects the is a two inhibitor and as a one inhibitor. Well, let's let's now go Into the real data and this is the point # three. What is basically happening here is that they make a comparison of the different trials with SGL people inhibitors that we mentioned before With the two studies recently published in the New England Journal of Medicine. With a short agree for him and in these two papers again recently published and I want to give you the at least the synthesis. The first paper was sort agree for him, AGI LT two and GLP one inhibitor in patients with diabetes in recent worsening of heart failure. And basically what they found is a lower total number of deaths from cardiovascular causes and and ah in hospitalization an urgent visit for heart failure when the user so to grief was in brussels placebo. This is the first paper and the second paper instead of heart failure was renal dysfunction and also had positive positive results. Then what it has been done here and I think the big bad presented these. What it has been done here is to compare the data of all these studies done with the L. G. L2 inhibitors with these two papers that I just presented of the new England Journal which is energy of the two. Energy to an inhibitor uh with the with sata gryphus in and this is what they say, what they say is this is very good drugs. Why? Because when you look at the number of events, this sort of Repossi not only was helpful as it was the best deal between him bitters into then points we mentioned, but it's much better in terms of myocardial infarction and stroke and in decreasing hemoglobin A one C in patients within all these functions. So what they are doing is Comparing all the data they're guilty to with this one and now they put together and it comes that maybe there are less events of strokes and myocardial infarction in the groups of acquisition. I feel how I feel. I feel confused because you're comparing apples with oranges here. I don't know in what you have to say. But let me finish Because now I am in point number four next one. And that is what is the explanation in here. There are several explanations are being given to what is happening. Uh First of all this D. L. S. G. O. T. Two. L. S. D. O. T. One Innovation groups are gonna like appetite increases and we know this can be some can have some significance in favor And patients of heart failure. And then there is experimental data that hypertension myocardial fibrosis with their GLP one innovation Maybe decrease experimental data. So there are reasons one may think that this is better and that person events were practically the same. So this is the conclusion. It is my final point point number five. Uh In addition to a reduction in nature in hemoglobin A one C levels in patients with advanced kidney disease, I mentioned this and uh and diabetes the relative increase of HLT one innovation with deadly force may provide greater protection from M. I. And stroke in the current available SGL people inhibitors that provide a lesser degree of HDL people and innovation. These observations suggest the dual SGL T. One and S. G. L. T. To innovation may provide an advantage over expect christian therapies in patients with diabetes mellitus. All these patients actually we're comparing the world diabetes link. How do you react? Oh I have very much your same confusion. This took me a long time to try to figure out where these people came from. Um I think the first question is is it different than the ones that are just SGL T2 inhibitors? Um I think certainly there are more likely to get a ongoing fluid loss in people with renal dysfunction with this. I don't know about the other mechanisms. Um I am also just very bewildered by taking people who who had worsening heart fair and diabetes. On the one hand, people who had stable um disease and real dysfunction on the other and putting them together. Those are two stable and unstable heart fair two very different situations. Um And in fact in the heart fair, worsening heart failure. The minority of people had a preserved ejection fraction. So then to come together and say this is a drug for half half. I actually think it is. I mean I'm not who bothered by the conclusion. I'm more bothered by the route to the conclusion that I am by the conclusion. Um And you know I I think this is a good family of drugs. Clearly it remains to be seen if this one is better than the other ones. I don't think we have data for that yet. Um But I do think that we should be just a little stern about the mix and match approach here and what we can conclude from it. Thank you lee None. I'm glad Lynn explained things to me because I was confused by the whole thing too. So um yeah there's a you know obviously we've got very good trial evidence now but the S. G. L. T. Two inhibitors and their effects and cardiovascular disease. So I think you know all of us should be using them more. I couldn't have followed the analysis very well and I have some concerns about it. But you know I think it's a it's an interesting addition to our armamentarium for treating these patients. Michael. You're not confused? No I was I was totally confused and now I feel better. I thought it was just a surgeon not understanding all this so I'm glad to hear that. And and Lynn were confused also. But what was obvious to me on the front end is Lindsay alluded to is it wasn't clear to me that this was pool herbal data. Uh There just seemed to be so much heterogeneity here. And the other thing I would say is that, you know, the benefit of SGL T two inhibitor seems so great nowadays that you almost wonder whether it's going to be in the water like flooring like fluoride. But I was heartened to hear that there was a trial that showed that S. G. L. T. Two hairs didn't work for something and that was covid. So I do think, you know, I'm totally supportive of this class of drugs but you know, we we should be discriminating and cautious. Thank you win. Yeah, not much more to add to that. The only other thing I would say is it's going to be time for clever people writing guidelines to assist the average cardiologist in understanding when to use these drugs which drug to use and what the totality of data suggests. So I think this is a call to action. Obviously the guideline folks to help us sort this through and come out with something. I don't know if linear and have any hints on when. I do want to mention that for most patients. Um we're talking about $500 a month for each uh S. C. L. T. Two inhibitor and security of AL certain. Um and you know, this is really really expensive and most patients can't afford it. And I don't think we're in a position to be able to tell them exactly why they should afford it if they also want to eat and you know, send their kids to school. So this is a problem as a health care system. It's fine to come up with things that work, but we're going to have to be able to deliver them without such a price tag. Okay, thank you very much The challenge of today. We have six minutes. So let me go into the last study, last studies, the galactic kitchen study. Uh It is effective ejection fraction on clinical outcomes in patients treated with no negative McCarville in the galactic HF, john sterling from the University of California san Francisco presented and he's being production and and I I think it's true that none of the studies that we know today in heart failure and I know trump's actually rejection for actually improves the patient improves but not necessarily dejection. So here we have this new type of drugs, the Maya true that actually worked in the cardiac sark amir enhancing the the the action. And one of them is the first one actually is um a competitive uh McCarville. Now here's the story uh this is the cosmic HF study in which in fact this drug was actually was used and it seemed that increased ejection fraction in that study but there were no outcome on the Galaxy catch every study that was just published. There were outcomes in this drug improve outcomes in patients with heart failure and reduce ejection fraction. What now is done here is to present how good it is with different ejection fraction. This is really the study that is presented the collective HF for study. And to make the long story short since I don't have much time, I will tell you that it works better with the low-ejection fraction is less than 25 and it doesn't work too well with ejection fractions about 35%. And then you have everything in between. So in summary, it's an interesting type of drugs and lower is the ejection fraction better is the way the drug works. Slim. Um I agree completely. And I have to say, I think it's really unfortunate that they didn't target these patients with the lower ejection fraction and the higher likelihood of benefit because there's not much enthusiasm out there for this drug. But we really need drugs for patients who continue to be symptomatic. Despite all the other therapies we have. And I think by casting the net too wide they may basically have lost the fish in this one because I do think it helps. Thank you on. Well, yeah, I mean and when you have patients who have that level of depressed ejection fraction, how many other options do you have? I mean at that point we put people on all the drugs that we can so to have something like this for the patients who are the worst off. There's a niche for this. Thank you, Michael. I don't have anything to add to Linz and ANne's comment valentine. Well, you don't send the patient for transplantation. Yeah, I sent it to me. No. 2. 1 right. All right. So when Yeah. Not not much more to add to that. I think it's fascinating that we're seeing now class of drugs that increases cardiac contract ability and actually reduces heart failure and without without an adverse effect on mortality. So, that's I think that's exciting. Just as the general cardiologist looking at this and I have nothing more to add final question to each of you think for a minute, Which is the study presented to the out of the eight. Did you feel most exciting, Michael? uh I've got the surgeon bias. So I would say Leo's three Lynn. Um I like the galactic, but I'm afraid the message won't be picked up. Um I think on the other side, the paradise was very important in showing us that we have to look at our patient populations and not give one drug to everybody. That's a good point on I like last 32 as well because it's a patients that I see with atrial fibrillation and so I think it's a fairly simple additional thing to do during surgery that has a positive impact. So I think I think that's probably gonna be one of the most impactful studies out of the ones we talked about today when and I would agree with both and and mike on this. I think Leo's was a fascinating study and it really starting tomorrow. I'm going to just remind my surgeons to just think about closing that left atrial appendage if they're in there for another reason. So it's impactful. Yeah. What I learned is that the site of leo's, what they learn is how we should look at trials and be very critical. A number of issues have been discussed today, which I think are quite important in terms of the what a child means, how it is designed, what kind of statistical methodologies being used? What is the actual impact relative versus absolute? And I think the studies that we had to the aid studies in each of them, there is something of this and I think that that to me is educational. Well, look, this is fantastic. Uh, I'm obliged to invite you again in the next time because you so well and I have not been any fights. This is the only problem I found in the meeting we had today. So you guys have been very homogeneous in terms of your deal. Thank you very much to all of you. I think this is a good tower and uh, I hope to see you soon again in a similar format. Thank you. Thanks very much. Thank you.
