Join Director of Mount Sinai Heart, Valentín Fuster, MD, PhD, MACC, as he discusses the Polypill and the SECURE trial, of which he is the chief investigator, at the European Society of Cardiology (ESC) Congress 2022.
The three-drug medication known as a “polypill” was found effective in preventing adverse events such as heart attacks or stroke in people who have previously had a heart attack, reducing cardiovascular mortality by 33 percent in this patient population.
Here Dr. Fuster discusses findings with Louise Bowman from the University of Oxford ESC 2022 in Barcelona. Hello and welcome to E. S. C. T. V. My name is Louise Bowman. I'm from the University of Oxford in the UK and I'm delighted to be joined by dr valentin Fuster from Mount Sinai, the chief investigator of the secure trial, the results of which were presented at E. S. C. 2020 just earlier today. So valentine, I wonder if we might start off by just talking a little bit about the background to the trial because I think it's been a life's work as far as I could tell. Yeah, the trial has a 15 year history And we began in 2007 when we found out that patients with heart attacks did not follow the medication profile necessary. We thought what is the answer if the problem is adherence to medications and we thought maybe a political and we develop a polypill which is very difficult because when you put three pills together in this case aspirin starting in an ace inhibitor, they interact with each other. So we had to develop with ferrer International Laboratories in Barcelona actually 50 polyp eels before we had one with aspirin Simvastatin and remit april. And then in a second phase we found that working with an important insurance company in the United States And dealing with actually 14,000 patients with heart attacks. We found we found retrospectively that those who took the medications did much better than those who didn't. This was retrospective. So finally the five, the last five years we decided to do this prospectively. And this is the secure trial which is basically to look at in a large cohort of patients with myocardial infarction if a polypill, which is a simple approach increases the adherence and decreases the cardiovascular events. This was the hypothesis of the study that was presented today. Excellent. And I think we're all in agreement that the idea of a polypill is is incredibly valuable. So perhaps you could um summarize for us the the overall trial results. And and some of the highlights from your interview. We look at cardiovascular events in 2500 patients in seven European countries with a median follow up of uh three years. We went up to six years, but the median follow up was three years. And what we found. Well, first the endpoints, the objective endpoints were troubles. Myocardial infarction, cardiovascular mortality stroke, or need for revascularization urgently. And the results frankly were very significant in favor of the polypill being superior. Now, what is interesting on the study is that the curse began to separate very early after the patients started and continued to separate at 34 years and maybe the results would even be more significant. We follow the patients longer. So the results were very significant. But what we were discussing actually with you before is that what was to me the most important validation that this is true Is that the 16 subgroups that were pre determined to see whether the political work, sex country type of events wherever in all 16 the trends of favoring the the polypill was there. So this gives you a sense of confidence that we are dealing with something that is real and we can talk in a minute. What are the implications how this compares with what we found on aspirin in the past, How this compares with the status. This is all part of the discussion. But I think the, the, the point I'd like to make is we are very happy. This is a real trial that you feel happy with the results. That actually may change practice. I mean that's basically what it is. And were there any aspects of the trial that surprised you? Anything that you don't have a clear answer to. I have many surprises first surprises most of the people that I talk to dealing with the trial didn't believe on the trial except the principal investigators and the patients. We had faith. This is like anything in life. We have so much data on adherence in our previous studies that I was convinced that the polypill would work, but not the rest of the world. That's the first surprise and the results frankly, they, I learned about it. I said you know it's important to have faith and few things and this is the surprising. But there is another surprise that I'm sure you are alluding to you say, well if you increase the adherence means that the cholesterol will drop, the blood pressure will drop, everything will be and this was not the case which we found on a previous study And this is worth discussing. We are using three medications here. one is an anti traumatic medication, aspirin. We hope it's working in the trial. But you don't you don't have any way to measure it except for heart attacks. Second you have remember april which stabilizes the blood vessel. We don't give the dose of Remy pill that really makes blood pressure to drop. So that's another aspect. We couldn't even say how this room april was working. But what's surprising is the LDL cholesterol was the same in both groups. And here's the question. Maybe the results have nothing to do with the starting and have to do with the aspirin, the remedial or it may have something to do with the statin. But through a plea, a tropic extent aspect that the status we know work. They can be anti traumatic, particularly after heart attacks. This good data in the literature, it can be anti inflammatory and not necessarily dropping the LDL cholesterol. And in this context, I want to make a very important point. The people who took the polypill freely. They took a higher dose of atorvastatin. The actually in the trial, which is interesting, 80 mg are suggested by guidelines versus 40 mg. Which after we look at the FDA and the Emma. They said you can go with 40 mg. And that's basically the story. So this is a surprise, no change in LDL. Yeah, absolutely. I think it's left a lot of people scratching their heads a bit. Um I wanted to ask you about the the process of the trial because my goodness me, you had to take undertake the trial during covid years and I'm sure there will have been a lot of challenges. What bits do you think Covid particularly imprinted on? Let me tell you this story. This is basically a five year of study. The first three years, there was no covid. So, and we enter most of the patients before Covid. The question is the follow up and in the follow up we lost mostly because Covid 14% of the patients and here's an important question that you brought up to me. And it's a fair question says, well you have 14% that you don't know what happened in. My answer to you is well, we know in partly what happened because we follow them until the last visit. So it's not that we said these patients don't are part of the child. They're part of the child for intention to treat. But the last visit just prior to covid in most of them. So the challenges of a trial like this are immense. And the two main challenges we found is first to develop a polypill. You hear a lot about politics. Everybody talks about polypill as how they make it and how pharmacologically the pill together access the pill separately because that's the key and there are not many pills. I know they have that property is a lot of work. And the second surprise is actually the LDL and the difficulties to me was copied and to convince the investigators that this was an important trial. It's certainly been a very hard time to, to run trials and and you, you suggested earlier, it would be interesting to think about what what the implications are. Where do you think this takes us now? Well, first of all, there is a polypill with simvastatin that with the value of adherence that is already approved by EMA and it's being sold already in some countries in europe and in latin America. That's number one this polypill before we talk openly, let's have EMA and FDA have a look and see if they approve it or they tell you know, we always like a second trial. My answer to the second trial is good luck followed. To make a trial like this. I have to tell you just for the sake of the investigators, we met almost daily for almost weekly for five years with the principal investigators, which is something that people don't pay attention to. If we had not done this. We wouldn't have trial or results today. So to develop a new trial, I think it's going to be a big, a big challenge. Now the question about the impact. I have two comments louis first with the results being as they are are as powerful or more than the results of aspirin following myocardial infarction. We did the first stallion aspirin in cardiac disease was the southerners being graphed. The study actually was the first And with aspirin you reached data of a decrease of events by about 30% 25% here. The decrease in cardiovascular mortality was 33 the second aspect and secondary prevention eri statins were the statins reached levels that were closer or perhaps less than what we find with the polypill. So what I'm really saying is if the polypill flies and the F. D. A. And M. A. Really approved we have in front of us something that is very simple, increases their hearings. But here comes the final common much cheaper. In fact the study when we developed we were thinking low income countries like happened with HIV and that is can we develop something that increases that hidden but it is affordable and we already have two pieces of information that this is cost effective and could be significantly much more affordable than just taking the pill separately and can you give us an indication of of that difference in cost proportionately? How much do you think it would reduce overall costs compared with the three tablets themselves? Well, I think obviously if you give a polypill you already know the the adherence will increase. Now going in the context of your question. I will tell you the following. We're talking about secondary prevention here very important because many people talk about polypill for primary prevention. Uh I don't disagree with the scientific hypothesis, but I have great trouble to those of you who walk around here and you are here saying I'm going to give you a polypill to prevent a heart attack. And my problem will be what polypill you need. How is your blood pressure? How is your cholesterol? Were in secondary prevention? We are obliged to give certain medications, which is how we took actually the polypill. But going further, it is possible the polypill begins to evolve on secondary prevention on in very high risk patients. And this is something that we keep in our minds, not necessarily heart attacks and this could have an impact. And finally, and I'm trying to answer your question from many variables. And finally, if you tell me, you asked me today what population, let's say in the United States today would have to take a polypill to prevent a second heart attack. And the answer is that 15-20% of the population in the United States will develop a heart attack. So, in a way the political, if it really move forward, I think could be a significant change in practice, that would have a significant implication in a large population. Everything I'm telling you, I'm sorry, is a wishful thinking based on the data, but that's what it is. Great. Well, I I know I've dominated the questions. We still have a few more minutes. So if anybody in the audience has any further questions, comments, thoughts for Dr foster, please do come to the microphone a valuable opportunity. In the meantime, perhaps my final question for you was aside from not doing the trial during covid years, is there anything you would have done differently if you were designing the trial? Now, is there anything that you think you might have made a difference? Is a very good point. No, if if if if we are convinced the second trial is necessary, I will tell you what I would like to do first. I would like to add a better blocker in patients with left ventricular dysfunction. And you say why you didn't you know why at the moment you put a better blocker with the polypill. I mentioned the pharmacogenetics changed drastically. We tested that. So this is why a polypill is not so simple as people think. So this would be a wish. The second thing, I don't think I would change the polypill with the present medications that we used to. But I would go into patients with, not necessarily type one myocardial infarction, but also non S. T elevation. Myocardial infarction, unstable angina. That would be the next step and perhaps a little bit further would be people at a very high risk that you cannot call it secondary prevention. But these are people who strong family histories, very high cholesterol levels and so forth. So the next trial would be to go further into the step of high risk population, not changing the medications that we already have and having wished the use of better blockers or other agents for decrease ventricular dysfunction. But we are very concerned And this leads to a final point, which I think is very important is the schizophrenia that we have today in medicine. On one hand, you read constantly about personalized medicine. And what I'm presenting here is completely in personalized medicine. And that is you have on one hand, simplicity and on the other hand, you have the patient with a special disease with a specific way to approach it. I feel both are necessary. Both are necessary. But if you deal with global health, I want simplicity. If you deal with the specific disease entities, you know, a type of amyloid disease that actually you know, is inherited. And then I think for personalized medicine, but let's be sure we understand global medicine. Global health needs simplicity and we try to do things that are not simple. I'm not against guidelines. But going to any guideline And you say, let me see what I have to do with a patient with this condition. You have 100 pages. Do you think you read them? You don't accept if you have a patient with trouble and the lawyers come to you. Maybe it's better you read what the guideline says. But we lack simplicity and I am very forward simplicity when you deal with something that is global health and it's a disease. # one, then we go into personalized medicine is a different issue. And the reason why I'm saying this is if we have to do another trial, one thing I would like to do is to continue to be simple not to be complicated. I think that's such a good point and it's something that in Oxford we feel extremely you do strongly about you. People started all of this with Collins and all and it was very fascinating. The first studies came from you people and certainly if you want a clear answer you have to keep it simple. We've got a question actually. My question was related to global health. So are there some limitations and if so how to overcome to allow everyone to profit from polypill? Also third world countries. I'm sorry but I need a polypill for my ear. So my question is so much noise that the high frequency I have trouble. Do you, can you repeat the question? Did you hear? I did. But my question was to have everyone accessing polypill. Are there limitations? Can everyone around the world access? I guess you know, economically speaking it might be a problem. Okay my friend. The first thing we have to difficult question. Not everybody can afford everything. And I think the first thing we have to go is to universal care, that that is, everybody is capable to have, what is necessary And I really want you to read a paper in the Lancet two years ago In the financial times. It is a commission that said, what is going to be held in the next 10 years and let me tell you the two issues they touch on the first tissue, obviously artificial intelligence and so forth, but was very fascinating. The first issue is Children go to education and really that's where we have to start in second Universal Care. They say if we do not address these two issues, we are offline and this is why, me personally, I am very involved On education in Children. We are following 50,000 Children around the world because I'm completely think the polypill is not the answer. The answer is actually education and education starts with people who listen and the people who listen are very young people. So, answering your question, I'm sorry to say everybody should afford to have a medication that is affordable and should be for everybody. But at least if it is not possible, this will be much cheaper than the present use of the three medications separately. We're over time, but I think we may have one more brief question perhaps based on the hypothesis that the increased adherence may be the reason for the benefits of the polypill. Have you checked in the trial? If it was really the increased adherence, the reason of the benefit or it's something else. It was a relation I cannot say cause effect. What was cause effect is the retrospective study that we did with Aetna insurance company. And then we have the focus trial that we found. Adherence is better with the polypill. So the fact that we found in adherence, which is very difficult to address. But the fact that we found adherence very much significant in the people taking the polypill. We have to conclude the hypothesis is probably correct, but I don't want to be 100% that everything was adherence. Their bias issues here and so forth. But I think adherence play at least a role. Perhaps an important role. Questions. What about primary prevention? About primary prevention? Not secondary. Oh well look, primary primary prevention. I don't believe on the polypill. I'm sorry. As I said before, if you bring somebody with a very high risk, I would say maybe this is the group. But tell me and I said this before. If everybody believes on a polypill in primary prevention, can you anybody tell me what the polypill should contain? What is your blood pressure? What is your cholesterol? In addition? Have you taken care of your health as smoking cessation, obesity, blood pressure. So the polypill, I'm sorry to say is not the answer. The polypill ways a cosmetic that is now ready to be used. But be sure we don't lose struck these people, we should go into the primary prevention and that's what I think education in Children is where it should begin. So I want to be very sure polypill is very sexy. The polypill very simple but that's not the answer. Well we are unfortunately out of time. I'm sure we could carry on discussing this for for a long time and we all look forward to seeing what the review of the trial brings Dr. Many. Congratulations thank you very much. And as I say 15 years of work very hard work. Well done. Thank you. Thank you very much.