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ESC 2019 Wrap-Up with Dr. Valentin Fuster
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ESC 2019 Wrap-Up with Dr. Valentin Fuster
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Segment:0 .
Good morning. We are in New York. This will be a good afternoon. We just came from Paris, that's the time over there, and good evening if you are watching from Australia. Well, I am Valentin Fuster from New York and I am here at Mount Sinai Medical Center. My task today is to give an overall view on a summary of the European Society of Cardiology meeting, or Congress, that we had in Paris and finished actually yesterday, also the World Congress of Cardiology.
It was a very complex meeting certainly for me because usually breaking trials, we have about 15, 20, this time we had 97. They were not called breaking trials. Their name was late breaking signs, which means that not everything presented were trials, some advances in sciences and so forth. I have to give thanks to the American College of Cardiology, to McGraw-Hill for sponsoring this event this morning.
I will be really happy to do the best I can since what I'm going to do in one hour is to summarize the 16 studies that I personally think were perhaps the most interesting ones, that maybe adding an inch, half an inch, to our present knowledge. Of these 16 studies, actually three of them relate to heart failure, three to coronary artery disease intervention, actually four, then we have coronary artery disease antithrombotic agents in acute coronary syndromes, there are three studies, there were three studies on coronary artery disease antithrombotics in a stable disease, and finally three other studies addressing health or modification of risk factors.
All together are 16 studies. There are obviously many others, but these are the ones that I decided to choose. The presentation is going to be by sections. It's not going to be by priority or what is the best study number one. It's not the way I will be presenting. I will start presenting the three studies that I thought were quite interesting related to heart failure.
Segment:1 Discussion of DAPA HF Trial.
Well, the first one, actually, is a study that was published in the European Heart Journal, but it was presented at the last minute with the results.
What was published in the European Heart Journal were actually the protocol how the study was designed and so forth. But at the last minute, the data was presented and it's quite fascinating data. Actually, this is the so-called DAPA-HF trial which was presented by Dr. John McMurray from Glasgow and it's about an SGLT2 inhibitor, dapagliflozin, how it does in patients with heart failure and reduced ejection fraction.
Half of the patients were diabetic, but interestingly, half of the patients were not. It's a very interesting question for the first time that it is being addressed. We all know that diabetes is frequently associated with heart failure. Therefore, the question was to entail 5,000 patients with heart failure and reduced ejection fraction-- rejection fraction was less than 40%.
These patients were randomized into dapagliflozin, 10 milligrams once daily, and then placebo, of course, with the standard care. The standard medical care was actually superb. Just to mention that 96% of the patients actually received either angiotensin receptor-neprilysin inhibitors or angiotensin receptor blockers, or ACE inhibitors. 94% received beta-blockers and 71% mineralocorticoid receptor antagonist.
These groups of patients were actually treated the best way that one can. Now, the study was a follow-up with a primary endpoint there was actually worsening of heart failure or death related to cardiovascular causes. These were the two primary endpoints. The follow-up was by 18 months. The results were fascinating. In fact, the worsening of heart failure or cardiovascular death, the two endpoints, actually was in 26%.
This composite endpoint was 26% in favor compared with the placebo. Then, if we go individually to the two separate endpoints, worsening of heart failure, the reduction was by 30%, and in terms of the reduction in cardiovascular death was 18%. So very, very, very striking. What is most striking is the results were not different in patients with heart failure alone, so there was no need to really have diabetes to show the results that I am presenting and that were presented yesterday.
There were adverse events, volume overload, renal dysfunction, etc., but there was no difference between the two groups, and certainly the issue of hypoglycemia and limb amputation was not a question, was not a problem, it was equally in both groups. Just summarizing this study, I think it's a fascinating study, it's a new approach that we have in patients with heart failure. It actually began with the diabetic population but now we are beginning to have a tremendous opportunity to have an impact in patients with heart failure as presented in this particular study.
Segment:2 Discussion of PARAGON HF Trial.
Having said this, now let me move into the second study everybody was waiting for. It's about the PARAGON-HF study. The PARAGON-HF study is really looking at angiotensin neprilysin inhibitors in patients with heart failure. We already know about patients with heart failure and low ejection fraction, but here we are talking about patients with preserved ejection fraction.
All the data available today is really combining these two drugs in the PARADIGM-HF trial in which it was shown that indeed hospitalization for heart failure or death related to cardiovascular causes was significantly decreased in these patients with heart failure and low ejection fraction. Now, the question is how they do in patients with regionally good ejection fraction considered 45% or higher.
Well, the patients that were randomized were actually near 5,000 patients with a New York Heart Association class two to four. The ejection fraction as I mentioned is 45% or higher. And then, these patients actually had elevated levels of natriuretic peptides. It is important to define for a moment heart failure with preserved ejection fraction. We all know what we are talking about, but it's important to focus our attention on a number of components.
Two of the most important components in this group of patients is myocardial hypertrophy and fibrosis, then hemodynamically we have diastolic compliance problem has impaired some systolic dysfunction, but just focusing on the hypertrophy and the fibrosis, that's where one of the focuses of the trial was, because neprilysin inhibitors actually release a number of peptides that have been considered to decrease fibrosis and hypertrophy.
This was actually one of the focuses of this study-- is to see, "Maybe we are going to do good in these patients." Well, the results actually were quite negative. The incidents of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group, 8.9% in the valsartan group. The same we can talk about hospitalization for heart failure, the same we can talk about New York Heart Association classification in the Kansas City cardiomyopathy score.
What we like to summarize this study is by saying, unfortunately, the sacubitril-valsartan did not result in a significant lower rate of total hospitalization for heart failure and death from cardiovascular causes among patients with heart failure and ejection fraction of 45%. This study was published in the New England Journal of Medicine. The principal investigator, Dr. Scott Solomon from the Brigham and Women's Hospital, and certainly a little bit of frustrating results.
Segment:3 Discussion of EVALUATE HF Trial.
This leads to a similar study in looking at a condition that is very often associated with heart failure and preserved ejection fraction. This is stiffness of the aorta. The study was very similar, was not part of the same study. This is the so-called evaluate heart failure study. Some of the investigators also participating in the other study that we just mentioned, and the title as was presented in JAMA is "Effect of Sacubitril-Valsartan vs Enalapril on Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction." We are all aware that aortic stiffness is becoming a very important risk factor for cardiovascular disease at the present time as shown recently in many, many studies.
It can be modified by these drugs, that actually and particularly sacubitril may decrease fibrosis and a smooth muscle cell proliferation as we mentioned in the heart, in this case it's in the aorta. The study was carried out in a group of patients. I think there were about 500 randomizing to the combination of sacubitril-valsartan and enalapril, and then followed for a period of 12 weeks.
Of these 500 patients, average age 67 years, in 12 weeks, nothing happened. I could say very little changes here and there, but the reality is the combination of sacubitril and valsartan failed in these groups of patients that had stiffness of the aorta. I'd like to emphasize that these patients actually had a reduced ejection fraction, so this is not the group of patients we would like to see, that are patients with preserved ejection fraction, and looking at the stiffness was not.
This is one problem. The other problem is I'm not sure how by the use of a combination of these two drugs you can change something that is so structural like the stiffness of the aorta in a period of 12 weeks. I would be very cautious by saying this is a negative study, but I would say this is a study that has to be carried on in patients with preserved ejection fraction and for a much longer period of time.
These are the three studies I present to you today in terms of heart failure. The first one, the DAPA-HF with dapagliflozin, very interesting. Let's now move into four studies related to coronary artery disease intervention. I was expecting actually it would be full of studies on TAVR, MVR, tricuspid and so forth. Well, I'm sorry to say that they cannot add more in those fields.
That's the reality. What was presented was okay, but certainly not adding too much into what we know.
Segment:4 Discussion of SYNTAXES Study.
Let's concentrate now into coronary artery disease intervention. The first two studies to me are fascinating, not scientifically fascinating but historically they are. The first study is the so-called SYNTAXES trial. Basically, it's the extension of the SYNTAX trial. The SYNTAX trial, you recall, we have five years of follow-up on a group of 1800 patients that had either three-vessel disease or left main disease, and they were randomized into PCI with paclitaxel-eluting stent or CABG.
In the results as they were presented at five years, it was a trend by decreasing all-cause mortality in the group with three-vessel disease but not in patients with left main disease. Here's the question what happened at 10 years of follow-up? What is fascinating to me is that 96% of the patients had follow-up at 10 years, something very difficult in any trial. This really requires a warm congratulations to everybody involved with the study.
Let's now go into the results. In terms of the overall mortality related to cardiovascular disease, in fact it's all-cause mortality, it was not a great difference, 27% in the paclitaxel-eluting stent group and 23% in the group treated with CABG. The significant difference is not in the left main. The significant difference is in three-vessel disease with a hazard ratio of 1.41, being highly significant.
What we can say is that according to the SYNTAX study that we already know the results at five years of follow-up, now we can say at 10 years of follow-up there is no question. CABG is superior to stenting in such patients, and particularly those with three-vessel disease with no difference in left main disease. I would say that in looking at the diabetes, there was not a statistical power to begin to talk about the diabetic population or not.
We published recently the combination of all the studies in which diabetes certainly was in favor of CABG, but I don't want to discuss this issue in this particular SYNTAXES follow-up of 10 years because there was not enough power to talk about diabetes.
Segment:5 Discussion of DANAMI-2 Trial.
The other study is fascinating. We all tend to talk about STEMI, stenting, STEMI, stenting, but do you know that 70% of the world uses fibrinolytic therapy?
It's better we open our minds and begin to ask the question again that was asked in the DANAMI-2 study. The DANAMI-2 study was a study, was a registration study in Denmark of patients with acute myocardial infarction. If you recall, most of the institutions actually received the patients but they had to transport the patients to another institution to have PCI. Some of them had fibrinolytic therapy in the institutions by themselves.
Certainly, this study was fascinating. I have to go back to history here. The first presentation of the DANAMI-2 was in 2002. Basically, these were patients who received fibrinolytic therapy in a hospital that didn't have intervention, and these were compared with the patients who had intervention in the hospitals as they could do it.
Some of the patients from the hospitals that could not do intervention were transferred to the other hospitals. The overall results were actually that intervention was better than fibrinolysis. If you go back to the paper, it's a general statement. It became much more focused, the second paper, which was actually the eight-year follow-up that was published in 2010. At that time, just to be more precise, we were talking about 1500 patients with STEMI in which actually more than 1,000 were at referred hospitals, and about 400 were in invasive hospitals.
Now, some of the patients were treated with fibrinolysis in these hospitals that didn't have capabilities for using invasive approaches, but some patients were transferred. The transfer was fascinating because the median time for a transfer from the moment of randomization was 67 minutes. This is out of any context, I know. When you interpret the DANAMI-2 study, it's unique because things were so well organized and so fast that at least one has to see the results in this context.
Well, the results were interesting, where 35% actually in terms of the primary endpoint, which was for the group in these hospitals that did fibrinolysis, versus 41% in the group that actually did intervention. Actually, I have to turn the data around because what they were talking about is a composite of reinfarction.
If I turn the data around, it was 35% in those who were intervened versus 41% in those who received fibrinolysis. Actually, the difference is not so significant if you look at, but it's due to the fact that the transfers were so well done. With these two endpoints, now in this meeting, what was presented was the 16 year follow-up. In the 16 year follow-up, even the results get a little closer.
Actually, in fact we talk about the composite of that or rehospitalization for myocardial infarction, 62% in the fibrinolytic group and 59% actually in the intervened group. It's just to show that if you are in a place in which you cannot do intervention but you do lytic therapy or you transfer the patients very quickly to the places that can do intervention, you can do very well.
This is Denmark. I'm not entirely sure we can talk the same about other countries, but this is one of the aspects that was worth to mention.
Segment:6 Discussion of COMPLETE Study.
Now, the next study that I'd like to talk about now is the so-called COMPLETE Study, after these two historical studies, the SYNTAX and the DANAMI. This is an important study because it's randomized. A patient comes with a STEMI, you do the culprit lesion or you do both, the culprit lesion and all the other lesions that appear to be significant.
How significance was interpreted in the study that I'm going to present? The significance was actually categorized if there were lesions of more than 70% or a positive FFR of less than 0.8 with lesions between 50 and 60%. What study are we talking about? The COMPLETE trial which was presented in New England Journal of Medicine as Complete Revascularization with Multivessel Disease PCI for Myocardial Infarction.
The first author is Dr. Shamir Mehta from the McMaster University, and I am now going to define the problem. Well, you know the issue. There are many observational studies, bias studies, some studies of the lesions, you have the culprit lesion but you have other lesions. You don't know if they are stable, if they are not, you don't know if they are significant, if they are not. It has been a confusion in the field. That's the reality.
Now, this study in my view is unique. The reason it's unique is actually randomized. It's a large number of patients that I will mention, and certainly the only question is, I'm not sure how severe these patients are, because the issue of risk, as you know, patients with shock, you are not going to follow this approach. You just go to the culprit lesion and that's it. One has to look at how severe it was.
Let's go into this study. This study was randomized STEMI patients, multi-vessel coronary artery disease, who actually undergo either culprit lesion PCI, or either complete revascularization with PCI in angiographically significant disease, as I define. It is important to know that one third or actually half of these patients, PCI done on the non-culprit lesions were done within the first 45 days, not at the time of the patient being in the hospital.
I will tell you there was no difference, just to start. If you do it in the hospital or you wait a little longer within 45 days, but I think this is important to actually define this study. Now, the first co-primary outcome was composite of cardiovascular death or myocardial infarction. The second co-primary outcome was the composite of cardiovascular death, myocardial infarction and ischemic revascularization. Actually, the median follow-up was three years.
Here were the results. First, we talk about the co-primary outcome, and I repeat, cardiovascular death or myocardial infarction was actually 7.8% in the complete revascularization group versus 10.5% in the culprit lesion alone. When you look at the second co-primary outcome, as I mentioned the composite of cardiovascular death, myocardial infarction, but you are ischemic revascularization, the results were more significant.
8.9% in the complete revascularization group versus 16.7% in the culprit lesion group. No difference. The timing of the complete revascularization, as I mentioned, whether it's done at the time of the patient being first admitted to the hospital or within the first 45 days. I think the summary is exciting. The question is, how sick these patients were? This is in the discussion.
The sense that one gets is that the patients were moderately sick, and I cannot go any further. But I think here's the challenge, when we talk about total revascularization versus culprit revascularization, I think the first question we have to ask ourselves, is this patient reasonably stable? If it is stable and the other vessels are significantly affected, total revascularization might be justified.
If the patient is in shock, it is not justified. If the patient is very mild disease in the other vessels, it's not justified. We cannot go any further, but this is where the discussion and the editorial comment really moves forward. We're beginning to have some sense about this important field because I will tell you, I have the figure. 50% of the patients that present with a STEMI have multi-vessel disease.
This is an issue that we have to deal every day with. I finished now this particular COMPLETE study. I still have one that goes into coronary artery disease intervention,
Segment:7 Discussion of BIOSTEMI Trial.
the biodegradable stents. Well, you know this story. If we go back biodegradable stents a year ago and we presented some information, the data was very equivocal and very worrisome. First, because the biodegrading takes more than two, three, four years, not take place in two, three months as it was thought, and the results were very questionable comparing biodegradable stents with other kinds of stents.
The study presented in Paris is a little bit different because of stents that are really very, very new. The study is called the BIOSTEMI study. It was actually published simultaneously in The Lancet with the title "Biodegradable Polymer Sirolimus-Eluting Stents versus Durable Polymer Everolimus-Eluting Stents in Patients with ST-Segment Elevation Myocardial Infarction." Well, the study was actually presented by Dr. Juan Iglesias, and he's from Geneva, University Hospital in Geneva, and it's actually a Swedish study...
Excuse me. A study from Switzerland entailing 10 different hospitals. It's a multi-center study as I mentioned. Patients had acute STEMI and they were eligible all to participate and they were randomly allocated into a biodegradable polymer sirolimus-eluting stent or had thin struts. The other was not biodegradable but also with a thin strut.
These are really the most advanced type of devices that we have today in terms of stents. They were compared actually one to one. The follow-up actually was 12 months, and the primary endpoint was very much targeted to the lesion failure. They consider lesion failure cardiac death. Could be, could be not. I think it's questionable. They also talk about certainly lesion revascularization and target-vessel infarction.
Well, let's go now into the results. First of all, let's say that the number of patients that participated in this study were 1300. They were appropriately randomized as I mentioned, and then the results were actually not too different. The primary composite endpoint of the target lesion failure in patients that were treated with the biodegradable stent was 4%, where in the others was actually 6%.
All due to a reduced ischemic-driven target. This was not related to that, this was not related to myocardial infarction. Here is the question. We have new stents with very narrow struts. This is the critical. The only differentiation that we have, one group is biodegradable and the other is not. Actually, thus far the difference, if any, is very trivial.
Now, one of the questions that this brought up, and I think is a very pertinent question, the follow-up of 12 months is very short. When you are talking about something that is biodegrading, you don't know how long it takes to biodegrade, so I think I would take this study as saying maybe all of our concerns about degradable stents are going away, and now we are looking more what about the long follow-up, how these stents do compared with the best stents available.
I think that's really the question that has to be answered in the future. It's interesting though how things advance. I remember discussing just a year ago how concerned we were about the biodegradable stents, and just in one year you see how things are turning around. Well, this is all about coronary artery disease intervention, two historical studies, the SYNTAXES and the DANAMI, the COMPLETE study, total revascularization, and the BIOSTEMI study comparing biodegradable stents versus not.
Now, we talk about antithrombotics. I can tell you, not easy to follow all of this. Many of these studies were actually published simultaneously, so you can go to the trials-- I certainly didn't go through the 97 studies, so I have to rely a lot on what is published. One thing that you see when something is published simultaneously, it's done fast. For example, you go to the statistics, they are there but you want to know more about it.
You go to the discussion and the discussion is repetitive. You go into the details of the study and you don't find them. This is an issue as editor of a journal, of JACC, that I have been very concerned and that is the simultaneous publications, that when it is presented is all done very fast. As you go to review them, you have lots of gaps that you cannot fill. This is what I'm saying.
This doesn't apply only to these antithrombotic studies I'm going to mention, it applies also to all the other studies that I present, not all but some that are simultaneous presentations. I say because you are going to read all these studies and you'll have a number of questions that I don't think are being answered, too quick.
Segment:8 Discussion of ISAR-REACT 5 Trial.
Let me go now into the studies. The first one is actually the ISAR-REACT 5 trial.
This study was presented in the New England Journal of Medicine and it's a very important one. It's an important question, Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. We all know based on previous studies, which I am not going to elucidate right now, that in acute coronary syndromes there's a high risk population in which Ticagrelor and Prasugrel have been found to be superior to Clopidogrel in working or intervening in these patients with acute coronary syndrome.
Which one of the two is better? This is what the study tried to answer. The presenter was Dr. Schüpke. He's from Munich, Germany. Let's now go into the actual study itself. The patients who had acute coronary syndromes, interesting, 40% were STEMI and 60% were non-STEMI. The patients received Ticagrelor or Prasugrel, and the primary endpoint was the composite of dead myocardial infarction or a stroke at one year.
The secondary endpoint was actually bleeding. Ticagrelor was done right away as the patient presented into the hospital as you do. Prasugrel, for a number of reasons, was given later after the anatomy was known. I'm trying to figure the dose. Therapy with Prasugrel was started with the loading dose of 60 milligrams and continue at a maintenance of 10 milligrams.
The loading dose of Ticagrelor was 180 milligrams and was maintenance 90 milligrams twice daily. This is actually what is being done routinely. Well, let's see what happened here. We had 4,000 patients, and actually, interestingly the winner was Prasugrel,. I just say this from the beginning, at all the endpoints, even the endpoint of bleeding which is the one you are always worried about, and actually it was the same between Ticagrelors and Prasugrel.
On the ischemic aspect, Prasugrel was superior. Let me give you the data. A primary endpoint event, remember that I mentioned myocardial infarction, death or stroke, 9.3% in the Ticagrelor group, 6.9% in the Prasugrel group. Individual components. Death, 4.5% Ticagrelor versus 3.7% Prasugrel. Myocardial infarction, 4.8% Ticagrelor, 3% Prasugrel.
Stroke 1.1% versus 1%. No difference in this case and certainly bleeding was the same. Here we have a situation that is interesting, and it's something that I think it's worth knowing. The lower incidence of problems actually with the Prasugrel, and the main aspect that was really very successful versus Ticagrelor was in myocardial infarction as the endpoint. What we are going to do in the future?
What is going to be the cost? What is going to be the availability? This is something that I cannot discuss at this time, but the data is a strong data and it's quite interesting.
Segment:9 Discussion of POPular Genetics Trial.
Well, the second study is actually very interesting. It's a genotype strategy study. This study is so-called POPular Genetics trial and was published also in the New England Journal of Medicine.
Here is the old question. When we give patients Ticagrelor... Excuse me-- When we give patients Clopidogrel, 30% of the patients, actually Clopidogrel doesn't work. One of the main reasons, it is being said has to do with the metabolism in the liver that can be addressed genetically. This is the question. This field has been going on for 10 years, but perhaps the study that I'm going to be presenting today is the most interesting one because of the large number of patients and the meticulous way that the study was actually done and it's trying to address this question.
Well, these patients all had STEMI, undergoing PCI with a stent implantation and one group received the Clopidogrel or the other drugs, but what was done is a study of genotyping, and to find out if the genotyping was negative for Clopidogrel or was not. And another group was treated with Prasugrel or Ticagrelor, completely independent.
I will tell you the results without going into too much detail, but basically, in the group of Clopidogrel they found the genetics were not adverse, the results were exactly the same than the group treated with Prasugrel or Ticagrelor. There's no need to present to you the specific data but just the concept is very important. That is maybe, maybe a quick genetic study which can be done right away can tell you what are you dealing with when you have these patients.
I think the study is interesting and certainly it opens the question again that how to address the issue of Clopidogrel that is not gone as the study's shown in patients who require PCI.
Segment:10 Discussion of POPular AGE Study.
Here comes another study that I think is interesting and it's also favoring Clopidogrel and it's patients over the age of 70. The study is called the POPular AGE study.
This is the story. You have a patient with an acute coronary syndrome, and as we said, the standard is Prasugrel versus Ticagrelor. The patient is over the age of 70 and the question is, these patients have more tendency to bleed and this is one of the problems, as you know, particularly with Ticagrelor and Prasugrel versus Clopidogrel. What do you do with these patients? No literature, because most of the studies avoided to use patients over the age of 70, 75.
Well, here we have a study that they look at such patients, 70, 75. Well, the study, I would like to actually summarize it where 1,000 elderly patients over the age of 70, the acute coronary syndrome was non-ST elevation and the patients were actually... A group would use Clopidogrel 75 milligrams once daily and the other group used Prasugrel or Ticagrelor.
This study I don't think was actually a randomized study. I have to say I should go into more detail, but I can tell you the results. And that is, the elderly population did well with Clopidogrel, and therefore it opens the question of whether without obsession of acute coronary syndrome, always Prasugrel versus Ticagrelor, whether we have patients over the age of 70, we might not be thinking twice that perhaps Clopidogrel is sufficient as with the genetic study.
What is happening in the acute coronary syndromes and in PCI in the thrombotic field is that the use of drugs now are really going... It's using all of them and see if we can go to those that are most feasible and perhaps less expensive. One of them is Clopidogrel that in the acute coronary syndrome has been highly questioned. Well, we have already two studies in which there is a possibility of salvaging Clopidogrel in acute coronary syndromes.
Having said this, these are the ISAR study, Ticagrelor versus Prasugrel, and then these two trials that Clopidogrel at least is emerging again.
Segment:11 Discussion of THEMIS and THEMIS PCI Study.
Now, we have coronary artery disease, antithrombotic agents in stable coronary artery disease. Just to tell you from the very beginning, we are talking about patients, and maybe a year ago, more than a year, might have PCI or CABG or might be talking with patients that never have an intervention.
Just focus your head for a moment into the kind of patient that comes to you chronically and the previous history of which you don't know much. Now, in the three studies they tell you specifics about the previous history but it's a chronic patient. Whatever previous history I talk happened a long time ago. All right. The first study that I'm going to present to you is the THEMIS-PCI study.
These are diabetic patients with a stable coronary artery disease, and stable means no myocardial infarction or stroke in the past. That's what they call stable. It doesn't mean they didn't have PCI or they didn't have CABG or they had nothing, but they didn't have myocardial infarction or stroke. Now what is the question? Why they are now going to look at what happens with these patients with Ticagrelor when the chronic patients we have been treating them with Clopidogrel?
The reason is because diabetes, we are all told that is similar to a high risk population, so they are using a little bit the thinking of what we do with acute coronary syndromes, that we use Prasugrel and Ticagrelor, we don't use actually Clopidogrel. Now, let's go to the diabetic population in chronic disease. Maybe we should use Ticagrelor rather than Clopidogrel. That's the question that is being answered.
I will tell you, a complex paper, to go over the paper in great detail, very complex. Actually, I will say to you that perhaps rather than going into a lot of detail, let me just say first it was published in The Lancet, our friend Deepak Bhatt was the principal investigator from the Brigham and Women's Hospital, and then I will tell you it was a multi-center study in 42 countries. Actually, there were a 1,000 institutions in 42 countries.
The number of patients that we are going to be discussing are all about 12,000 patients and so forth. It's a large study with a follow-up of three years. Now, I want to define THEMIS, T-H-E-M-I-S. I told you are PCI patients, CABG patients and are patients with no intervention, but all of them did not have myocardial infarction or stroke. Here, I am only talking about the PCI group. Forget about all the others.
This is called THEMIS-PCI because in a moment I will talk about the THEMIS with all the patients I presented. This is just PCI. What was found was very, very borderline, very, very borderline because here's the story. These patients were actually assigned to Ticagrelor and aspirin versus aspirin alone. This is the question that is being asked.
These are patients that had the intervention a long time ago. You say, "Why they are not on Clopidogrel?" Well, this is a long time ago. This is what I'm actually emphasizing. Then, this is what happened. When you look at the data, here you have the primary efficacy endpoint which is actually a composite of cardiovascular death, myocardial infarction or stroke, was actually 7.5% in one group and 8.6% on the other.
Ticagrelor was better than actually the patients who did not have Ticagrelor, all patients who were on aspirin. 7.5% versus 8.6%, not much. Then, when you go into intracranial hemorrhage, also in this case the Ticagrelor did a little bit worse than the control group. It's 2% versus 1%. You have here 1% on one side favor Ticagrelor, 1% on the other side it favors not Ticagrelor.
Next paper. The next paper actually is in the New England Journal, and it's actually the same THEMIS study but here are all the groups I presented to you CABG, PCI in the past, coronary artery disease in the past, but no infarction, no stroke. And then, look at the diabetic population again. These patients actually are more diluted because they are not following PCI.
The results were quite negative here. Here, you cannot say even to consider. This is common sense. This is all diluted with all the patients, chronic coronary artery disease, so my friends give aspirin. That's the story.
Segment:12 Discussion of AFIRE Study.
Well, now we are getting into the next aspect that is actually the third one, that is the AFIRE study. Let me explain to you this.
Still antithrombotic therapy in chronic coronary artery disease. Now the patient has atrial fibrillation and the patient had in the past whatever you like, CABG, PCI, infarction, stroke, here's everything, all-comers. The patient in this case has atrial fibrillation and has coronary artery disease, any kind that you want, but it's a chronic case. The question is, "What do you do?" Well-- I will tell you what the guidelines say just recently.
We are not going about a year ago. The guidelines say be careful with using anticoagulants plus two inhibitors if the patient is reasonably off the PCI soon. Use it for a short period of time but then you go for six weeks or so with an anticoagulant plus a platelet inhibitor. And after a few weeks when you are getting into the chronic stage, you may use monotherapy, this is interesting because I didn't know, and you use an anticoagulant alone.
I'm talking about coronary artery disease long after whatever happened before. This is in the guidelines. So I went to the guidelines and said, "Where this is coming from?" I didn't know. Well, this is a Dutch cohort study. It was actually... They have this fantastic resource of every patient getting into a system in which you can know everything.
What they found is that monotherapy in patients with chronic coronary artery disease using an anticoagulant, that's good. This is in general. What this study here is about, they use a particular anticoagulant which is rivaroxoban. Rivaroxaban is coming in coronary artery disease from all fronts in chronic coronary artery disease. This is one.
The patient has atrial fibrillation, long coronary artery disease, and here's the question. Here is patients who use monotherapy, 10 to 15 milligrams of rivaroxaban. How so low? Japan. People are smaller. So, 10 to 15 milligrams they use, not 20 milligrams. The other was a combination of rivaroxaban plus a single platelet inhibitor. The majority of patients were actually patients who use aspirin.
It's a non-inferiority study with a primary safety endpoint in which very much focused on the issue of bleeding. Let me make the long story short. That is, when this study was done, the primary efficacy endpoint that is ischemic events, there was no much difference between monotherapy, rivaroxaban alone, versus rivaroxaban and aspirin. It's nice to know because this is coming from other studies. But in bleeding, there was a difference and that is the combination was 2.76% of bleeding versus monotherapy 1.6%. Here, the results, what they suggest is in patients with chronic coronary artery disease we should begin to talk about rivaroxaban as a monotherapy.
Remember, there's no aspirin here. It's a new coming culture that is evolving very slowly from a number of studies, it's how these new oral anticoagulants can do good for patients with coronary artery disease as well as patients with atrial fibrillation because they had both. This is the study.
Segment:13 Discussion of Metabolic Surgery and Cardiovascular Outcomes in Type 2 Diabetes.
Now, I have three other studies that have to do with alteration of risk factors.
The first one I think is important. You have an obese patient and the patient is diabetic, and you say, "Well, bariatric surgery— what we call now metabolic surgery, as you know— versus the usual medical therapy." There's a lot published in the literature, but certainly not a study as large as this one. Again, it started at the Cleveland Clinic which are really pioneers in this field.
We are talking about over 2,000 patients that actually were randomized into metabolic surgery versus non-surgical approach. The randomization was one to five. That is, many more patients had diabetes and obesity. I don't want to call this a strict randomization because it was not, but certainly it's a large number of patients in which they looked actually at the endpoints that we like to look at.
That is about all-cause mortality, cardiovascular mortality, heart failure, nephropathy, atrial fibrillation, all of this was looked at. The results were outstanding for bariatric surgery, I have to say to you. I can give you figures of any parameter, 30% versus 47%, 17% versus 10%. I'm talking about they look at six parameters. To tell you the difference in endpoints is very significant on any endpoint when you do bariatric surgery versus you follow these patients, obese patients with a BMI of more than 30 and patients who actually have diabetes, type two diabetes, all being treated medically the best they can.
I think this study is telling us something, that we should think and think again about bariatric surgery. But there is something missing here. What about side effects of bariatric surgery? That's the key issue here because it's very... Well, I can tell you the data. The data is 28% had some side effect. This puts this study a little bit into question. What were the side effects?
In fact, not very significant because we thought cardiac events 1%, renal failure less than 1%, requiring abdominal surgical intervention again 5%, death 1%, endoscopy required because something is not right 16%, are side effects but 28%. When you look at it, it's not so bad. I think we have to change our view and begin to look at this much more seriously in patients with diabetes and obesity.
Segment:14 Discussion of LDL SBP Trial.
Here we are in the last two studies with risk factors. I have seven minutes left I guess. This is a very interesting one because of the concept. The concept is very important, and this concept is beginning to evolve in the genetic field. That is, you look at blood pressure and you look at LDL in all the studies, five years follow-up. Now, we begin to see 10 years follow-up. But what about if you have the genetic background of the patient that fits with the blood pressure?
And the genetics don't change. They may change, epigenetics, but let's assume the genetics don't change. A given blood pressure with a genetic variable being identified may prolong what you find in a short term in a long term. I'm just talking generally speaking, it's a new approach, and this is what was used in this study. This study actually was published in JAMA. The main investigator from the University of Cambridge at the United Kingdom was Dr. Brian Ference.
They use a very important enterprise. This is what the biobanks are going to be in the future, very critical, very critical. They use the UK biobank, to me, the number one in the world. This is followed by biobanks that are being developed in China and in other places. I am not saying that I am pro-British now in the biobank, but certainly the data that is beginning to evolve from that biobank is fascinating because everything is surveilled genetically and any risk factor is surveilled with the most recent genetic tools that we have available.
Well, they have half a million participants that were involved in the UK biobank. They look at LDL cholesterol and systolic blood pressure. And then, they look at the whole genetic background of all the different numbers of blood pressure, and they ended up saying, "A blood pressure of this kind with this genetic variable, a blood pressure of this kind with this genetic variable, let's see what happens with these patients over a short period of time in terms of cardiovascular events, and we will be able to prolong what would happen in a long term but just looking this concept." Well, the results are fascinating but I can give you one example, just to give you the example.
You have, for example, you drop LDL cholesterol by 14 milligrams in a patient who has a high cholesterol, LDL you drop it by 14 milligrams and blood pressure by five millimeters of mercury. Okay, you follow this patient for about a year or two and you compare with a patient who has an LDL cholesterol that is normal and a blood pressure that is normal. And you see a difference, let's say a difference in terms of cardiovascular events between 4% and 2% at one year.
Now, you use these genetics and then you prolong forever and it's a 50% reduction but you can imagine when you go for not one year, for 50 years, and then you see the impact. This really brings us into statistics. When we talk about absolute impact versus relative impact, it's very, very important. These genetic tools are going to enable us to really prolong what we see in a short time by looking at the whole genetic profile and trying to see what the impact will be in a long term.
This is also what is done statistically with the Bayesian approach. The Bayesian approach is basically accumulating events over a period of time but it's still during the period that you're studying the patient. Here, it's prolonged after the period that you have been studying the patient. I think this is actually very fascinating, and the study basically says that if you use the DASH diet in which you have a little bit of lower LDL and a little bit of salt, they prolong here an incredible impact when you go into genetics that just at the beginning may be very little but for a long period of time has a significant impact.
It's a conceptual paper, which I think is quite interesting.
Segment:15 Discussion of HOPE 4 Study.
Here's the final one which is actually the paper was published in The Lancet. This comes from the HOPE-4 study. This is a study presented by the group in Colombia because it was done in two countries, Colombia and Malaysia, and these are the auspices of Dr. Yusuf that is involved with the PURE study. The study is actually fascinating and we all know about it.
We are talking about 14,000 individuals with poorly controlled blood pressure from 30 communities in Colombia and Malaysia. This is very simple. You put a system there that not necessarily are doctors. It's a system of people that are non-physician health workers. They work together and they work simply in making things to happen. What the paper is showing is what we are beginning to see in many community studies when in fact are run by health workers and not necessarily just by physicians.
We can actually direct the studies. The results that they present here were very significant in terms of how impact you may have in reducing blood pressure following the Framingham score and so forth and impacting in these patients by just following a completely different approach. That is not getting rid of physicians but really enhancing the health system with other people who do the work. I don't go into the details.
I finished my presentation today, at least the best I could do in saying that are 16 studies out of 97, I have here nine or 10 more that I could talk about it, but at least what we can remember is that in heart failure the use of dapagliflozin can be quite interesting a drug that's being used for diabetes. In the intervention studies, it's fascinating the SYNTAX and the DANAMI-2 how they have been followed for a long period of time, but most important, the COMPLETE study perhaps in medium risk patients with STEMI that we can do revascularize the whole system or at least the arteries that are non-culprit that have significant disease.
And then in acute coronary syndromes, I think the most important study maybe was the Ticagrelor verus Prasugrel when we saw the role of Prasugrel. And then we have in stable coronary artery disease we have the fact that the diabetes may be similar to coronary artery disease but don't start using Prasugrels and Ticagrelors particularly in the chronic patient because you don't see a difference. And the issue of the AFIRE study with rivaroxaban at a low dose in patients with chronic coronary artery disease, it touched the other studies that are coming out using rivaroxaban in patients with coronary artery disease.
And finally, in terms of the risk factor profile, bariatric surgery is number one, the genetic approach to long follow-up of patients when we have a short follow-up and the importance of community work done by people in the health system that can really put together what is shown in the study that I just presented. Well, thank you very much for your attention. Thank you all.
APPLAUSE:
Segment:0 .
Good morning. We are in New York. This will be a good afternoon. We just came from Paris, that's the time over there, and good evening if you are watching from Australia. Well, I am Valentin Fuster from New York and I am here at Mount Sinai Medical Center. My task today is to give an overall view on a summary of the European Society of Cardiology meeting, or Congress, that we had in Paris and finished actually yesterday, also the World Congress of Cardiology.
It was a very complex meeting certainly for me because usually breaking trials, we have about 15, 20, this time we had 97. They were not called breaking trials. Their name was late breaking signs, which means that not everything presented were trials, some advances in sciences and so forth. I have to give thanks to the American College of Cardiology, to McGraw-Hill for sponsoring this event this morning.
I will be really happy to do the best I can since what I'm going to do in one hour is to summarize the 16 studies that I personally think were perhaps the most interesting ones, that maybe adding an inch, half an inch, to our present knowledge. Of these 16 studies, actually three of them relate to heart failure, three to coronary artery disease intervention, actually four, then we have coronary artery disease antithrombotic agents in acute coronary syndromes, there are three studies, there were three studies on coronary artery disease antithrombotics in a stable disease, and finally three other studies addressing health or modification of risk factors.
All together are 16 studies. There are obviously many others, but these are the ones that I decided to choose. The presentation is going to be by sections. It's not going to be by priority or what is the best study number one. It's not the way I will be presenting. I will start presenting the three studies that I thought were quite interesting related to heart failure.
Segment:1 Discussion of DAPA HF Trial.
Well, the first one, actually, is a study that was published in the European Heart Journal, but it was presented at the last minute with the results.
What was published in the European Heart Journal were actually the protocol how the study was designed and so forth. But at the last minute, the data was presented and it's quite fascinating data. Actually, this is the so-called DAPA-HF trial which was presented by Dr. John McMurray from Glasgow and it's about an SGLT2 inhibitor, dapagliflozin, how it does in patients with heart failure and reduced ejection fraction.
Half of the patients were diabetic, but interestingly, half of the patients were not. It's a very interesting question for the first time that it is being addressed. We all know that diabetes is frequently associated with heart failure. Therefore, the question was to entail 5,000 patients with heart failure and reduced ejection fraction-- rejection fraction was less than 40%.
These patients were randomized into dapagliflozin, 10 milligrams once daily, and then placebo, of course, with the standard care. The standard medical care was actually superb. Just to mention that 96% of the patients actually received either angiotensin receptor-neprilysin inhibitors or angiotensin receptor blockers, or ACE inhibitors. 94% received beta-blockers and 71% mineralocorticoid receptor antagonist.
These groups of patients were actually treated the best way that one can. Now, the study was a follow-up with a primary endpoint there was actually worsening of heart failure or death related to cardiovascular causes. These were the two primary endpoints. The follow-up was by 18 months. The results were fascinating. In fact, the worsening of heart failure or cardiovascular death, the two endpoints, actually was in 26%.
This composite endpoint was 26% in favor compared with the placebo. Then, if we go individually to the two separate endpoints, worsening of heart failure, the reduction was by 30%, and in terms of the reduction in cardiovascular death was 18%. So very, very, very striking. What is most striking is the results were not different in patients with heart failure alone, so there was no need to really have diabetes to show the results that I am presenting and that were presented yesterday.
There were adverse events, volume overload, renal dysfunction, etc., but there was no difference between the two groups, and certainly the issue of hypoglycemia and limb amputation was not a question, was not a problem, it was equally in both groups. Just summarizing this study, I think it's a fascinating study, it's a new approach that we have in patients with heart failure. It actually began with the diabetic population but now we are beginning to have a tremendous opportunity to have an impact in patients with heart failure as presented in this particular study.
Segment:2 Discussion of PARAGON HF Trial.
Having said this, now let me move into the second study everybody was waiting for. It's about the PARAGON-HF study. The PARAGON-HF study is really looking at angiotensin neprilysin inhibitors in patients with heart failure. We already know about patients with heart failure and low ejection fraction, but here we are talking about patients with preserved ejection fraction.
All the data available today is really combining these two drugs in the PARADIGM-HF trial in which it was shown that indeed hospitalization for heart failure or death related to cardiovascular causes was significantly decreased in these patients with heart failure and low ejection fraction. Now, the question is how they do in patients with regionally good ejection fraction considered 45% or higher.
Well, the patients that were randomized were actually near 5,000 patients with a New York Heart Association class two to four. The ejection fraction as I mentioned is 45% or higher. And then, these patients actually had elevated levels of natriuretic peptides. It is important to define for a moment heart failure with preserved ejection fraction. We all know what we are talking about, but it's important to focus our attention on a number of components.
Two of the most important components in this group of patients is myocardial hypertrophy and fibrosis, then hemodynamically we have diastolic compliance problem has impaired some systolic dysfunction, but just focusing on the hypertrophy and the fibrosis, that's where one of the focuses of the trial was, because neprilysin inhibitors actually release a number of peptides that have been considered to decrease fibrosis and hypertrophy.
This was actually one of the focuses of this study-- is to see, "Maybe we are going to do good in these patients." Well, the results actually were quite negative. The incidents of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group, 8.9% in the valsartan group. The same we can talk about hospitalization for heart failure, the same we can talk about New York Heart Association classification in the Kansas City cardiomyopathy score.
What we like to summarize this study is by saying, unfortunately, the sacubitril-valsartan did not result in a significant lower rate of total hospitalization for heart failure and death from cardiovascular causes among patients with heart failure and ejection fraction of 45%. This study was published in the New England Journal of Medicine. The principal investigator, Dr. Scott Solomon from the Brigham and Women's Hospital, and certainly a little bit of frustrating results.
Segment:3 Discussion of EVALUATE HF Trial.
This leads to a similar study in looking at a condition that is very often associated with heart failure and preserved ejection fraction. This is stiffness of the aorta. The study was very similar, was not part of the same study. This is the so-called evaluate heart failure study. Some of the investigators also participating in the other study that we just mentioned, and the title as was presented in JAMA is "Effect of Sacubitril-Valsartan vs Enalapril on Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction." We are all aware that aortic stiffness is becoming a very important risk factor for cardiovascular disease at the present time as shown recently in many, many studies.
It can be modified by these drugs, that actually and particularly sacubitril may decrease fibrosis and a smooth muscle cell proliferation as we mentioned in the heart, in this case it's in the aorta. The study was carried out in a group of patients. I think there were about 500 randomizing to the combination of sacubitril-valsartan and enalapril, and then followed for a period of 12 weeks.
Of these 500 patients, average age 67 years, in 12 weeks, nothing happened. I could say very little changes here and there, but the reality is the combination of sacubitril and valsartan failed in these groups of patients that had stiffness of the aorta. I'd like to emphasize that these patients actually had a reduced ejection fraction, so this is not the group of patients we would like to see, that are patients with preserved ejection fraction, and looking at the stiffness was not.
This is one problem. The other problem is I'm not sure how by the use of a combination of these two drugs you can change something that is so structural like the stiffness of the aorta in a period of 12 weeks. I would be very cautious by saying this is a negative study, but I would say this is a study that has to be carried on in patients with preserved ejection fraction and for a much longer period of time.
These are the three studies I present to you today in terms of heart failure. The first one, the DAPA-HF with dapagliflozin, very interesting. Let's now move into four studies related to coronary artery disease intervention. I was expecting actually it would be full of studies on TAVR, MVR, tricuspid and so forth. Well, I'm sorry to say that they cannot add more in those fields.
That's the reality. What was presented was okay, but certainly not adding too much into what we know.
Segment:4 Discussion of SYNTAXES Study.
Let's concentrate now into coronary artery disease intervention. The first two studies to me are fascinating, not scientifically fascinating but historically they are. The first study is the so-called SYNTAXES trial. Basically, it's the extension of the SYNTAX trial. The SYNTAX trial, you recall, we have five years of follow-up on a group of 1800 patients that had either three-vessel disease or left main disease, and they were randomized into PCI with paclitaxel-eluting stent or CABG.
In the results as they were presented at five years, it was a trend by decreasing all-cause mortality in the group with three-vessel disease but not in patients with left main disease. Here's the question what happened at 10 years of follow-up? What is fascinating to me is that 96% of the patients had follow-up at 10 years, something very difficult in any trial. This really requires a warm congratulations to everybody involved with the study.
Let's now go into the results. In terms of the overall mortality related to cardiovascular disease, in fact it's all-cause mortality, it was not a great difference, 27% in the paclitaxel-eluting stent group and 23% in the group treated with CABG. The significant difference is not in the left main. The significant difference is in three-vessel disease with a hazard ratio of 1.41, being highly significant.
What we can say is that according to the SYNTAX study that we already know the results at five years of follow-up, now we can say at 10 years of follow-up there is no question. CABG is superior to stenting in such patients, and particularly those with three-vessel disease with no difference in left main disease. I would say that in looking at the diabetes, there was not a statistical power to begin to talk about the diabetic population or not.
We published recently the combination of all the studies in which diabetes certainly was in favor of CABG, but I don't want to discuss this issue in this particular SYNTAXES follow-up of 10 years because there was not enough power to talk about diabetes.
Segment:5 Discussion of DANAMI-2 Trial.
The other study is fascinating. We all tend to talk about STEMI, stenting, STEMI, stenting, but do you know that 70% of the world uses fibrinolytic therapy?
It's better we open our minds and begin to ask the question again that was asked in the DANAMI-2 study. The DANAMI-2 study was a study, was a registration study in Denmark of patients with acute myocardial infarction. If you recall, most of the institutions actually received the patients but they had to transport the patients to another institution to have PCI. Some of them had fibrinolytic therapy in the institutions by themselves.
Certainly, this study was fascinating. I have to go back to history here. The first presentation of the DANAMI-2 was in 2002. Basically, these were patients who received fibrinolytic therapy in a hospital that didn't have intervention, and these were compared with the patients who had intervention in the hospitals as they could do it.
Some of the patients from the hospitals that could not do intervention were transferred to the other hospitals. The overall results were actually that intervention was better than fibrinolysis. If you go back to the paper, it's a general statement. It became much more focused, the second paper, which was actually the eight-year follow-up that was published in 2010. At that time, just to be more precise, we were talking about 1500 patients with STEMI in which actually more than 1,000 were at referred hospitals, and about 400 were in invasive hospitals.
Now, some of the patients were treated with fibrinolysis in these hospitals that didn't have capabilities for using invasive approaches, but some patients were transferred. The transfer was fascinating because the median time for a transfer from the moment of randomization was 67 minutes. This is out of any context, I know. When you interpret the DANAMI-2 study, it's unique because things were so well organized and so fast that at least one has to see the results in this context.
Well, the results were interesting, where 35% actually in terms of the primary endpoint, which was for the group in these hospitals that did fibrinolysis, versus 41% in the group that actually did intervention. Actually, I have to turn the data around because what they were talking about is a composite of reinfarction.
If I turn the data around, it was 35% in those who were intervened versus 41% in those who received fibrinolysis. Actually, the difference is not so significant if you look at, but it's due to the fact that the transfers were so well done. With these two endpoints, now in this meeting, what was presented was the 16 year follow-up. In the 16 year follow-up, even the results get a little closer.
Actually, in fact we talk about the composite of that or rehospitalization for myocardial infarction, 62% in the fibrinolytic group and 59% actually in the intervened group. It's just to show that if you are in a place in which you cannot do intervention but you do lytic therapy or you transfer the patients very quickly to the places that can do intervention, you can do very well.
This is Denmark. I'm not entirely sure we can talk the same about other countries, but this is one of the aspects that was worth to mention.
Segment:6 Discussion of COMPLETE Study.
Now, the next study that I'd like to talk about now is the so-called COMPLETE Study, after these two historical studies, the SYNTAX and the DANAMI. This is an important study because it's randomized. A patient comes with a STEMI, you do the culprit lesion or you do both, the culprit lesion and all the other lesions that appear to be significant.
How significance was interpreted in the study that I'm going to present? The significance was actually categorized if there were lesions of more than 70% or a positive FFR of less than 0.8 with lesions between 50 and 60%. What study are we talking about? The COMPLETE trial which was presented in New England Journal of Medicine as Complete Revascularization with Multivessel Disease PCI for Myocardial Infarction.
The first author is Dr. Shamir Mehta from the McMaster University, and I am now going to define the problem. Well, you know the issue. There are many observational studies, bias studies, some studies of the lesions, you have the culprit lesion but you have other lesions. You don't know if they are stable, if they are not, you don't know if they are significant, if they are not. It has been a confusion in the field. That's the reality.
Now, this study in my view is unique. The reason it's unique is actually randomized. It's a large number of patients that I will mention, and certainly the only question is, I'm not sure how severe these patients are, because the issue of risk, as you know, patients with shock, you are not going to follow this approach. You just go to the culprit lesion and that's it. One has to look at how severe it was.
Let's go into this study. This study was randomized STEMI patients, multi-vessel coronary artery disease, who actually undergo either culprit lesion PCI, or either complete revascularization with PCI in angiographically significant disease, as I define. It is important to know that one third or actually half of these patients, PCI done on the non-culprit lesions were done within the first 45 days, not at the time of the patient being in the hospital.
I will tell you there was no difference, just to start. If you do it in the hospital or you wait a little longer within 45 days, but I think this is important to actually define this study. Now, the first co-primary outcome was composite of cardiovascular death or myocardial infarction. The second co-primary outcome was the composite of cardiovascular death, myocardial infarction and ischemic revascularization. Actually, the median follow-up was three years.
Here were the results. First, we talk about the co-primary outcome, and I repeat, cardiovascular death or myocardial infarction was actually 7.8% in the complete revascularization group versus 10.5% in the culprit lesion alone. When you look at the second co-primary outcome, as I mentioned the composite of cardiovascular death, myocardial infarction, but you are ischemic revascularization, the results were more significant.
8.9% in the complete revascularization group versus 16.7% in the culprit lesion group. No difference. The timing of the complete revascularization, as I mentioned, whether it's done at the time of the patient being first admitted to the hospital or within the first 45 days. I think the summary is exciting. The question is, how sick these patients were? This is in the discussion.
The sense that one gets is that the patients were moderately sick, and I cannot go any further. But I think here's the challenge, when we talk about total revascularization versus culprit revascularization, I think the first question we have to ask ourselves, is this patient reasonably stable? If it is stable and the other vessels are significantly affected, total revascularization might be justified.
If the patient is in shock, it is not justified. If the patient is very mild disease in the other vessels, it's not justified. We cannot go any further, but this is where the discussion and the editorial comment really moves forward. We're beginning to have some sense about this important field because I will tell you, I have the figure. 50% of the patients that present with a STEMI have multi-vessel disease.
This is an issue that we have to deal every day with. I finished now this particular COMPLETE study. I still have one that goes into coronary artery disease intervention,
Segment:7 Discussion of BIOSTEMI Trial.
the biodegradable stents. Well, you know this story. If we go back biodegradable stents a year ago and we presented some information, the data was very equivocal and very worrisome. First, because the biodegrading takes more than two, three, four years, not take place in two, three months as it was thought, and the results were very questionable comparing biodegradable stents with other kinds of stents.
The study presented in Paris is a little bit different because of stents that are really very, very new. The study is called the BIOSTEMI study. It was actually published simultaneously in The Lancet with the title "Biodegradable Polymer Sirolimus-Eluting Stents versus Durable Polymer Everolimus-Eluting Stents in Patients with ST-Segment Elevation Myocardial Infarction." Well, the study was actually presented by Dr. Juan Iglesias, and he's from Geneva, University Hospital in Geneva, and it's actually a Swedish study...
Excuse me. A study from Switzerland entailing 10 different hospitals. It's a multi-center study as I mentioned. Patients had acute STEMI and they were eligible all to participate and they were randomly allocated into a biodegradable polymer sirolimus-eluting stent or had thin struts. The other was not biodegradable but also with a thin strut.
These are really the most advanced type of devices that we have today in terms of stents. They were compared actually one to one. The follow-up actually was 12 months, and the primary endpoint was very much targeted to the lesion failure. They consider lesion failure cardiac death. Could be, could be not. I think it's questionable. They also talk about certainly lesion revascularization and target-vessel infarction.
Well, let's go now into the results. First of all, let's say that the number of patients that participated in this study were 1300. They were appropriately randomized as I mentioned, and then the results were actually not too different. The primary composite endpoint of the target lesion failure in patients that were treated with the biodegradable stent was 4%, where in the others was actually 6%.
All due to a reduced ischemic-driven target. This was not related to that, this was not related to myocardial infarction. Here is the question. We have new stents with very narrow struts. This is the critical. The only differentiation that we have, one group is biodegradable and the other is not. Actually, thus far the difference, if any, is very trivial.
Now, one of the questions that this brought up, and I think is a very pertinent question, the follow-up of 12 months is very short. When you are talking about something that is biodegrading, you don't know how long it takes to biodegrade, so I think I would take this study as saying maybe all of our concerns about degradable stents are going away, and now we are looking more what about the long follow-up, how these stents do compared with the best stents available.
I think that's really the question that has to be answered in the future. It's interesting though how things advance. I remember discussing just a year ago how concerned we were about the biodegradable stents, and just in one year you see how things are turning around. Well, this is all about coronary artery disease intervention, two historical studies, the SYNTAXES and the DANAMI, the COMPLETE study, total revascularization, and the BIOSTEMI study comparing biodegradable stents versus not.
Now, we talk about antithrombotics. I can tell you, not easy to follow all of this. Many of these studies were actually published simultaneously, so you can go to the trials-- I certainly didn't go through the 97 studies, so I have to rely a lot on what is published. One thing that you see when something is published simultaneously, it's done fast. For example, you go to the statistics, they are there but you want to know more about it.
You go to the discussion and the discussion is repetitive. You go into the details of the study and you don't find them. This is an issue as editor of a journal, of JACC, that I have been very concerned and that is the simultaneous publications, that when it is presented is all done very fast. As you go to review them, you have lots of gaps that you cannot fill. This is what I'm saying.
This doesn't apply only to these antithrombotic studies I'm going to mention, it applies also to all the other studies that I present, not all but some that are simultaneous presentations. I say because you are going to read all these studies and you'll have a number of questions that I don't think are being answered, too quick.
Segment:8 Discussion of ISAR-REACT 5 Trial.
Let me go now into the studies. The first one is actually the ISAR-REACT 5 trial.
This study was presented in the New England Journal of Medicine and it's a very important one. It's an important question, Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. We all know based on previous studies, which I am not going to elucidate right now, that in acute coronary syndromes there's a high risk population in which Ticagrelor and Prasugrel have been found to be superior to Clopidogrel in working or intervening in these patients with acute coronary syndrome.
Which one of the two is better? This is what the study tried to answer. The presenter was Dr. Schüpke. He's from Munich, Germany. Let's now go into the actual study itself. The patients who had acute coronary syndromes, interesting, 40% were STEMI and 60% were non-STEMI. The patients received Ticagrelor or Prasugrel, and the primary endpoint was the composite of dead myocardial infarction or a stroke at one year.
The secondary endpoint was actually bleeding. Ticagrelor was done right away as the patient presented into the hospital as you do. Prasugrel, for a number of reasons, was given later after the anatomy was known. I'm trying to figure the dose. Therapy with Prasugrel was started with the loading dose of 60 milligrams and continue at a maintenance of 10 milligrams.
The loading dose of Ticagrelor was 180 milligrams and was maintenance 90 milligrams twice daily. This is actually what is being done routinely. Well, let's see what happened here. We had 4,000 patients, and actually, interestingly the winner was Prasugrel,. I just say this from the beginning, at all the endpoints, even the endpoint of bleeding which is the one you are always worried about, and actually it was the same between Ticagrelors and Prasugrel.
On the ischemic aspect, Prasugrel was superior. Let me give you the data. A primary endpoint event, remember that I mentioned myocardial infarction, death or stroke, 9.3% in the Ticagrelor group, 6.9% in the Prasugrel group. Individual components. Death, 4.5% Ticagrelor versus 3.7% Prasugrel. Myocardial infarction, 4.8% Ticagrelor, 3% Prasugrel.
Stroke 1.1% versus 1%. No difference in this case and certainly bleeding was the same. Here we have a situation that is interesting, and it's something that I think it's worth knowing. The lower incidence of problems actually with the Prasugrel, and the main aspect that was really very successful versus Ticagrelor was in myocardial infarction as the endpoint. What we are going to do in the future?
What is going to be the cost? What is going to be the availability? This is something that I cannot discuss at this time, but the data is a strong data and it's quite interesting.
Segment:9 Discussion of POPular Genetics Trial.
Well, the second study is actually very interesting. It's a genotype strategy study. This study is so-called POPular Genetics trial and was published also in the New England Journal of Medicine.
Here is the old question. When we give patients Ticagrelor... Excuse me-- When we give patients Clopidogrel, 30% of the patients, actually Clopidogrel doesn't work. One of the main reasons, it is being said has to do with the metabolism in the liver that can be addressed genetically. This is the question. This field has been going on for 10 years, but perhaps the study that I'm going to be presenting today is the most interesting one because of the large number of patients and the meticulous way that the study was actually done and it's trying to address this question.
Well, these patients all had STEMI, undergoing PCI with a stent implantation and one group received the Clopidogrel or the other drugs, but what was done is a study of genotyping, and to find out if the genotyping was negative for Clopidogrel or was not. And another group was treated with Prasugrel or Ticagrelor, completely independent.
I will tell you the results without going into too much detail, but basically, in the group of Clopidogrel they found the genetics were not adverse, the results were exactly the same than the group treated with Prasugrel or Ticagrelor. There's no need to present to you the specific data but just the concept is very important. That is maybe, maybe a quick genetic study which can be done right away can tell you what are you dealing with when you have these patients.
I think the study is interesting and certainly it opens the question again that how to address the issue of Clopidogrel that is not gone as the study's shown in patients who require PCI.
Segment:10 Discussion of POPular AGE Study.
Here comes another study that I think is interesting and it's also favoring Clopidogrel and it's patients over the age of 70. The study is called the POPular AGE study.
This is the story. You have a patient with an acute coronary syndrome, and as we said, the standard is Prasugrel versus Ticagrelor. The patient is over the age of 70 and the question is, these patients have more tendency to bleed and this is one of the problems, as you know, particularly with Ticagrelor and Prasugrel versus Clopidogrel. What do you do with these patients? No literature, because most of the studies avoided to use patients over the age of 70, 75.
Well, here we have a study that they look at such patients, 70, 75. Well, the study, I would like to actually summarize it where 1,000 elderly patients over the age of 70, the acute coronary syndrome was non-ST elevation and the patients were actually... A group would use Clopidogrel 75 milligrams once daily and the other group used Prasugrel or Ticagrelor.
This study I don't think was actually a randomized study. I have to say I should go into more detail, but I can tell you the results. And that is, the elderly population did well with Clopidogrel, and therefore it opens the question of whether without obsession of acute coronary syndrome, always Prasugrel versus Ticagrelor, whether we have patients over the age of 70, we might not be thinking twice that perhaps Clopidogrel is sufficient as with the genetic study.
What is happening in the acute coronary syndromes and in PCI in the thrombotic field is that the use of drugs now are really going... It's using all of them and see if we can go to those that are most feasible and perhaps less expensive. One of them is Clopidogrel that in the acute coronary syndrome has been highly questioned. Well, we have already two studies in which there is a possibility of salvaging Clopidogrel in acute coronary syndromes.
Having said this, these are the ISAR study, Ticagrelor versus Prasugrel, and then these two trials that Clopidogrel at least is emerging again.
Segment:11 Discussion of THEMIS and THEMIS PCI Study.
Now, we have coronary artery disease, antithrombotic agents in stable coronary artery disease. Just to tell you from the very beginning, we are talking about patients, and maybe a year ago, more than a year, might have PCI or CABG or might be talking with patients that never have an intervention.
Just focus your head for a moment into the kind of patient that comes to you chronically and the previous history of which you don't know much. Now, in the three studies they tell you specifics about the previous history but it's a chronic patient. Whatever previous history I talk happened a long time ago. All right. The first study that I'm going to present to you is the THEMIS-PCI study.
These are diabetic patients with a stable coronary artery disease, and stable means no myocardial infarction or stroke in the past. That's what they call stable. It doesn't mean they didn't have PCI or they didn't have CABG or they had nothing, but they didn't have myocardial infarction or stroke. Now what is the question? Why they are now going to look at what happens with these patients with Ticagrelor when the chronic patients we have been treating them with Clopidogrel?
The reason is because diabetes, we are all told that is similar to a high risk population, so they are using a little bit the thinking of what we do with acute coronary syndromes, that we use Prasugrel and Ticagrelor, we don't use actually Clopidogrel. Now, let's go to the diabetic population in chronic disease. Maybe we should use Ticagrelor rather than Clopidogrel. That's the question that is being answered.
I will tell you, a complex paper, to go over the paper in great detail, very complex. Actually, I will say to you that perhaps rather than going into a lot of detail, let me just say first it was published in The Lancet, our friend Deepak Bhatt was the principal investigator from the Brigham and Women's Hospital, and then I will tell you it was a multi-center study in 42 countries. Actually, there were a 1,000 institutions in 42 countries.
The number of patients that we are going to be discussing are all about 12,000 patients and so forth. It's a large study with a follow-up of three years. Now, I want to define THEMIS, T-H-E-M-I-S. I told you are PCI patients, CABG patients and are patients with no intervention, but all of them did not have myocardial infarction or stroke. Here, I am only talking about the PCI group. Forget about all the others.
This is called THEMIS-PCI because in a moment I will talk about the THEMIS with all the patients I presented. This is just PCI. What was found was very, very borderline, very, very borderline because here's the story. These patients were actually assigned to Ticagrelor and aspirin versus aspirin alone. This is the question that is being asked.
These are patients that had the intervention a long time ago. You say, "Why they are not on Clopidogrel?" Well, this is a long time ago. This is what I'm actually emphasizing. Then, this is what happened. When you look at the data, here you have the primary efficacy endpoint which is actually a composite of cardiovascular death, myocardial infarction or stroke, was actually 7.5% in one group and 8.6% on the other.
Ticagrelor was better than actually the patients who did not have Ticagrelor, all patients who were on aspirin. 7.5% versus 8.6%, not much. Then, when you go into intracranial hemorrhage, also in this case the Ticagrelor did a little bit worse than the control group. It's 2% versus 1%. You have here 1% on one side favor Ticagrelor, 1% on the other side it favors not Ticagrelor.
Next paper. The next paper actually is in the New England Journal, and it's actually the same THEMIS study but here are all the groups I presented to you CABG, PCI in the past, coronary artery disease in the past, but no infarction, no stroke. And then, look at the diabetic population again. These patients actually are more diluted because they are not following PCI.
The results were quite negative here. Here, you cannot say even to consider. This is common sense. This is all diluted with all the patients, chronic coronary artery disease, so my friends give aspirin. That's the story.
Segment:12 Discussion of AFIRE Study.
Well, now we are getting into the next aspect that is actually the third one, that is the AFIRE study. Let me explain to you this.
Still antithrombotic therapy in chronic coronary artery disease. Now the patient has atrial fibrillation and the patient had in the past whatever you like, CABG, PCI, infarction, stroke, here's everything, all-comers. The patient in this case has atrial fibrillation and has coronary artery disease, any kind that you want, but it's a chronic case. The question is, "What do you do?" Well-- I will tell you what the guidelines say just recently.
We are not going about a year ago. The guidelines say be careful with using anticoagulants plus two inhibitors if the patient is reasonably off the PCI soon. Use it for a short period of time but then you go for six weeks or so with an anticoagulant plus a platelet inhibitor. And after a few weeks when you are getting into the chronic stage, you may use monotherapy, this is interesting because I didn't know, and you use an anticoagulant alone.
I'm talking about coronary artery disease long after whatever happened before. This is in the guidelines. So I went to the guidelines and said, "Where this is coming from?" I didn't know. Well, this is a Dutch cohort study. It was actually... They have this fantastic resource of every patient getting into a system in which you can know everything.
What they found is that monotherapy in patients with chronic coronary artery disease using an anticoagulant, that's good. This is in general. What this study here is about, they use a particular anticoagulant which is rivaroxoban. Rivaroxaban is coming in coronary artery disease from all fronts in chronic coronary artery disease. This is one.
The patient has atrial fibrillation, long coronary artery disease, and here's the question. Here is patients who use monotherapy, 10 to 15 milligrams of rivaroxaban. How so low? Japan. People are smaller. So, 10 to 15 milligrams they use, not 20 milligrams. The other was a combination of rivaroxaban plus a single platelet inhibitor. The majority of patients were actually patients who use aspirin.
It's a non-inferiority study with a primary safety endpoint in which very much focused on the issue of bleeding. Let me make the long story short. That is, when this study was done, the primary efficacy endpoint that is ischemic events, there was no much difference between monotherapy, rivaroxaban alone, versus rivaroxaban and aspirin. It's nice to know because this is coming from other studies. But in bleeding, there was a difference and that is the combination was 2.76% of bleeding versus monotherapy 1.6%. Here, the results, what they suggest is in patients with chronic coronary artery disease we should begin to talk about rivaroxaban as a monotherapy.
Remember, there's no aspirin here. It's a new coming culture that is evolving very slowly from a number of studies, it's how these new oral anticoagulants can do good for patients with coronary artery disease as well as patients with atrial fibrillation because they had both. This is the study.
Segment:13 Discussion of Metabolic Surgery and Cardiovascular Outcomes in Type 2 Diabetes.
Now, I have three other studies that have to do with alteration of risk factors.
The first one I think is important. You have an obese patient and the patient is diabetic, and you say, "Well, bariatric surgery— what we call now metabolic surgery, as you know— versus the usual medical therapy." There's a lot published in the literature, but certainly not a study as large as this one. Again, it started at the Cleveland Clinic which are really pioneers in this field.
We are talking about over 2,000 patients that actually were randomized into metabolic surgery versus non-surgical approach. The randomization was one to five. That is, many more patients had diabetes and obesity. I don't want to call this a strict randomization because it was not, but certainly it's a large number of patients in which they looked actually at the endpoints that we like to look at.
That is about all-cause mortality, cardiovascular mortality, heart failure, nephropathy, atrial fibrillation, all of this was looked at. The results were outstanding for bariatric surgery, I have to say to you. I can give you figures of any parameter, 30% versus 47%, 17% versus 10%. I'm talking about they look at six parameters. To tell you the difference in endpoints is very significant on any endpoint when you do bariatric surgery versus you follow these patients, obese patients with a BMI of more than 30 and patients who actually have diabetes, type two diabetes, all being treated medically the best they can.
I think this study is telling us something, that we should think and think again about bariatric surgery. But there is something missing here. What about side effects of bariatric surgery? That's the key issue here because it's very... Well, I can tell you the data. The data is 28% had some side effect. This puts this study a little bit into question. What were the side effects?
In fact, not very significant because we thought cardiac events 1%, renal failure less than 1%, requiring abdominal surgical intervention again 5%, death 1%, endoscopy required because something is not right 16%, are side effects but 28%. When you look at it, it's not so bad. I think we have to change our view and begin to look at this much more seriously in patients with diabetes and obesity.
Segment:14 Discussion of LDL SBP Trial.
Here we are in the last two studies with risk factors. I have seven minutes left I guess. This is a very interesting one because of the concept. The concept is very important, and this concept is beginning to evolve in the genetic field. That is, you look at blood pressure and you look at LDL in all the studies, five years follow-up. Now, we begin to see 10 years follow-up. But what about if you have the genetic background of the patient that fits with the blood pressure?
And the genetics don't change. They may change, epigenetics, but let's assume the genetics don't change. A given blood pressure with a genetic variable being identified may prolong what you find in a short term in a long term. I'm just talking generally speaking, it's a new approach, and this is what was used in this study. This study actually was published in JAMA. The main investigator from the University of Cambridge at the United Kingdom was Dr. Brian Ference.
They use a very important enterprise. This is what the biobanks are going to be in the future, very critical, very critical. They use the UK biobank, to me, the number one in the world. This is followed by biobanks that are being developed in China and in other places. I am not saying that I am pro-British now in the biobank, but certainly the data that is beginning to evolve from that biobank is fascinating because everything is surveilled genetically and any risk factor is surveilled with the most recent genetic tools that we have available.
Well, they have half a million participants that were involved in the UK biobank. They look at LDL cholesterol and systolic blood pressure. And then, they look at the whole genetic background of all the different numbers of blood pressure, and they ended up saying, "A blood pressure of this kind with this genetic variable, a blood pressure of this kind with this genetic variable, let's see what happens with these patients over a short period of time in terms of cardiovascular events, and we will be able to prolong what would happen in a long term but just looking this concept." Well, the results are fascinating but I can give you one example, just to give you the example.
You have, for example, you drop LDL cholesterol by 14 milligrams in a patient who has a high cholesterol, LDL you drop it by 14 milligrams and blood pressure by five millimeters of mercury. Okay, you follow this patient for about a year or two and you compare with a patient who has an LDL cholesterol that is normal and a blood pressure that is normal. And you see a difference, let's say a difference in terms of cardiovascular events between 4% and 2% at one year.
Now, you use these genetics and then you prolong forever and it's a 50% reduction but you can imagine when you go for not one year, for 50 years, and then you see the impact. This really brings us into statistics. When we talk about absolute impact versus relative impact, it's very, very important. These genetic tools are going to enable us to really prolong what we see in a short time by looking at the whole genetic profile and trying to see what the impact will be in a long term.
This is also what is done statistically with the Bayesian approach. The Bayesian approach is basically accumulating events over a period of time but it's still during the period that you're studying the patient. Here, it's prolonged after the period that you have been studying the patient. I think this is actually very fascinating, and the study basically says that if you use the DASH diet in which you have a little bit of lower LDL and a little bit of salt, they prolong here an incredible impact when you go into genetics that just at the beginning may be very little but for a long period of time has a significant impact.
It's a conceptual paper, which I think is quite interesting.
Segment:15 Discussion of HOPE 4 Study.
Here's the final one which is actually the paper was published in The Lancet. This comes from the HOPE-4 study. This is a study presented by the group in Colombia because it was done in two countries, Colombia and Malaysia, and these are the auspices of Dr. Yusuf that is involved with the PURE study. The study is actually fascinating and we all know about it.
We are talking about 14,000 individuals with poorly controlled blood pressure from 30 communities in Colombia and Malaysia. This is very simple. You put a system there that not necessarily are doctors. It's a system of people that are non-physician health workers. They work together and they work simply in making things to happen. What the paper is showing is what we are beginning to see in many community studies when in fact are run by health workers and not necessarily just by physicians.
We can actually direct the studies. The results that they present here were very significant in terms of how impact you may have in reducing blood pressure following the Framingham score and so forth and impacting in these patients by just following a completely different approach. That is not getting rid of physicians but really enhancing the health system with other people who do the work. I don't go into the details.
I finished my presentation today, at least the best I could do in saying that are 16 studies out of 97, I have here nine or 10 more that I could talk about it, but at least what we can remember is that in heart failure the use of dapagliflozin can be quite interesting a drug that's being used for diabetes. In the intervention studies, it's fascinating the SYNTAX and the DANAMI-2 how they have been followed for a long period of time, but most important, the COMPLETE study perhaps in medium risk patients with STEMI that we can do revascularize the whole system or at least the arteries that are non-culprit that have significant disease.
And then in acute coronary syndromes, I think the most important study maybe was the Ticagrelor verus Prasugrel when we saw the role of Prasugrel. And then we have in stable coronary artery disease we have the fact that the diabetes may be similar to coronary artery disease but don't start using Prasugrels and Ticagrelors particularly in the chronic patient because you don't see a difference. And the issue of the AFIRE study with rivaroxaban at a low dose in patients with chronic coronary artery disease, it touched the other studies that are coming out using rivaroxaban in patients with coronary artery disease.
And finally, in terms of the risk factor profile, bariatric surgery is number one, the genetic approach to long follow-up of patients when we have a short follow-up and the importance of community work done by people in the health system that can really put together what is shown in the study that I just presented. Well, thank you very much for your attention. Thank you all.
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