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AHA 2018 Wrap-Up with Dr. Valentin Fuster
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AHA 2018 Wrap-Up with Dr. Valentin Fuster
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Segment:0 .
DR. VALENTIN FUSTER: Thank you very much for being here today this morning, and giving me the opportunity to discuss what went on in the American Heart Association meeting in Chicago. It was interesting, many presentations in terms of trials. What I'm going to do is to discuss eight different studies, which at least to me, were the most interesting ones.
DR. VALENTIN FUSTER: The first three were positive results. One is the REDUCE-IT trial on high triglyceride levels. The second is the Akcea trial on dropping ApolipoA:, a very challenging aspect that we face. The other was the long-term follow-up of the FREEDOM trial, which was diabetic patients with multi-vessel disease, I think eight-year follow-up. Then we have two interesting studies, which although were not positive, they gave us a lot of thought about mechanisms.
DR. VALENTIN FUSTER: One is the so-called CIRT study on methotrexate as an anti-inflammatory drug in patients with coronary atherosclerotic disease, and then there was the so-called DECLARE TIMI-58, which is the use of the new inhibitors of the glucose uptake by the urinary tract, dapagliflozin. It was a negative trial, but certainly gets again into the issue of mechanisms.
DR. VALENTIN FUSTER: Then there were two trials that were quite amazing to me. One is the use of Omega-3, and the other is the use of Vitamin D, and I will only tell you the headlines of The Washington Post and the headlines of The New York Times. The headline of The Washington Post is "Great Findings in DHA," and said like Omega-3 and Vitamin D preventing cardiovascular disease and cancer.
DR. VALENTIN FUSTER: The headlines of The New York Times are completely the opposite. "Failure of Omega-3 and Vitamin D"-- do not prevent cardiovascular disease and cancer. I think we have to comment on that because it is really one of the issues that is affecting the public today, is how things are transferring to the press and what the press captures. And, finally, I want to talk for about ten minutes about the cholesterol guidelines and to give a summary of what I think are the most critical points of that.
DR. VALENTIN FUSTER: So, we have close to an hour, maybe less, and let me begin.
Segment:1 Discussion of REDUCE-IT Trial.
DR. VALENTIN FUSTER: To me, the most interesting study is the one I am going to discuss right now is the so-called REDUCE-IT trial. It was presented by Dr. Deepak Bhatt from the Brigham and Women's Hospital in Boston and it came out in The New England Journal: "Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia." Let me give you a little bit of background.
DR. VALENTIN FUSTER: As you know, fibrates, niacin, Omega-3 have failed on preventing cardiovascular disease in people with high triglyceride levels. But there's a study from Japan in 2007, the so-called Jelly study. They use EPA, eicosapentaenoic acid, that today many people take as one of the supplements. They use a good dose, 1.8 grams daily, a high dose, together with statins and they decrease cardiovascular events by 19 percent.
DR. VALENTIN FUSTER: This is 2007. Nothing happened since then, apparently, what I heard is that, it was very difficult to do a trial and whatever it was, but the people, the so-called REDUCE-IT investigators, they decided to approach the trial properly based on the study of 2007. What they did is they use a purified form of EPA and this is called, the name of the drug is icosapent ethyl, whatever that means, but the fact of the matter is the results were actually spectacular and let me present it to you.
DR. VALENTIN FUSTER: These are eight thousand people from eleven countries, patients, who actually had cardiovascular disease, or they had diabetes and other risk factors. These were people at high risk of cardiovascular disease. What they did is that all of them had received statin therapy-- just to tell you that the average LDL was 75 mg/dl, so these are people who actually had normal LDL levels, high risk for cardiovascular disease but they had high triglycerides.
DR. VALENTIN FUSTER: I don't know how high is 135 mg/dl, but they were between 135 and 500 mg/dl. So it is questionable to call high 135 but that's exactly how the patients entered into this study, and they received a high dose of 2 grams twice daily. This is 4 grams a day vs. placebo. The primary endpoint had five different variables-- death, non-fatal MI, non-fatal stroke, coronary revascularization or unstable angina.
DR. VALENTIN FUSTER: Then the secondary endpoints were the very critical ones, the first three I mentioned-- cardiovascular, they had non-fatal MI, or non-fatal stroke. They're usually the opposite of what is being done. The results were as follows. First of all, the triglyceride levels actually dropped only 19 percent. So if you really look at triglycerides as the main driving force, really the results were not very significant, but they dropped 19 percent.
DR. VALENTIN FUSTER: The follow-up was five years. Here we have the primary endpoint, they dropped the event rate from 22 percent in the placebo group to 17 percent in the group treated with icosapent ethyl. The secondary endpoints were also from 15 percent to 11 percent. The results were actually very significant and even the rate of cardiovascular death, it dropped from 5 percent to 4 percent; it was also significant.
DR. VALENTIN FUSTER: We are dealing with a large number of patients, eight thousand. Then the bleeding events were exactly the same, with a little bit more of atrial fibrillation in the treated group, 3 percent vs. 2 percent, but certainly the results were quite significant, and the question is, what is going on here? It is difficult to attach the results to the triglyceride levels, and the drop in triglycerides because it dropped, as I mentioned, 19 percent.
DR. VALENTIN FUSTER: So here we have a drug that is doing something but probably has nothing to do with the original driving force, which was to drop triglycerides, which had been seen in preliminary studies and that's how really the focus of the trial was. Now they have been looking at these and it's a drug that apparently is antithrombotic, it stabilizes coronary plaques, is anti-inflammatory, so it's one of these drugs, EPA basically, a purified EPA, that does something very good when it's given.
DR. VALENTIN FUSTER: Now the question here is, what do we do with this drug? Because if you say, I have a patient with high triglycerides and let me use it to drop them, you're not going to have a great success because 19 percent drop is not so significant. So now a number of trials are going to be developed with this drug, but I am not entirely sure that triglycerides are going to be the focus, frankly. Now if you have a patient with high triglyceride levels, just use it, I guess.
DR. VALENTIN FUSTER: But it's difficult to really pinpoint when it's a drug that has so multi-effects and the one that you wanted to see, the most significant, it doesn't really play that way. However, the reality is, this is a drug that you find when you go to any store. Not in the purified form as it is here and certainly, to me was the best interesting trial that presented. At the end we will have some discussion. I prefer to move into the eight subjects.
DR. VALENTIN FUSTER: Anyway, this was number one.
Segment:2 Discussion of AKCEA Phase 2 Trial.
DR. VALENTIN FUSTER: The other trial that I thought was important was the one dealing with ApolipoA: and let me discuss it. This is the so-called
AKCEA-APOA: -LRx Study, and this was presented by somebody who has been working on ApolipoA: very obsessively for twenty years, Dr. Tsimikas, Sotirios, from the University of San Diego, he's an LPA guy. Actually, he developed the company who made this trial happen, and I know him very well, he really believes UNINTELLIGIBLE:. About ApolipoA:, you all know, it appears to be a significant risk factor, certainly in Asian countries and in this country, the United States, certainly in a number of young people without other risk factors ApolipoA: has been identified in some cases as being important.
AKCEA-APOA: So this is all that we can say. A large number of sites in the United States, Canada, Europe, enrolled nearly 300 patients, and again with a trial risk-- they had preexisting coronary artery disease or myocardial infarction, peripheral arterial disease or stroke and TIAs. They have an elevated level of triglycerides and they also had an elevated level of ApolipoA: and what they did is, this was actually a Phase II study.
AKCEA-APOA: What is the right dose? Is the drug harmful? I mean, this is basically what the study was about. So they used four different dosages and this is a subcutaneous approach like the PCSK-9. In one case they use it, the maximal dose was 20 mgs daily, and the minimal dose was 20 mgs monthly. Then there are two dosages in between. They followed these people for actually about twenty-seven weeks, and they were treated aggressively for six months.
AKCEA-APOA: So, it was six months treatment and then the follow-up for a few more months. The results were spectacular, I must say. We don't have clinical endpoints, but we certainly know what happened with ApolipoA: and with the minimal dose, monthly 200-- 20 mgs monthly, was 35 percent drop but was 80 percent when they used it weekly. So to drop ApolipoA: 80 percent, to me is the miracle of the year because you cannot achieve that with anything I know.
AKCEA-APOA: About secondary endpoints, LDL also dropped somehow and there were side effects just at the injection site-- 25 percent of the people had some erythema in the injection site. And 4.6 percent discontinued the drug for one reason or another but this is the same as in the placebo. Then they described a case that committed suicide, you know, but who knows, but the study was presented very openly on every aspect.
AKCEA-APOA: Now the question is, it's great we have a drug that can drop ApolipoA:, what about the next step? What is going to be the next clinical trial? And it's hard to know because to find these patients with very high ApolipoA: was very difficult. When I told you many institutions participated and only three hundred patients were able to be entered, so...
AKCEA-APOA: I don't know what type of patients are going to be in the next study but certainly all of us see patients with high ApolipoA: levels, and it's going to be fascinating where this goes. But I think at least there is a sense of optimism or of positive thinking that maybe we're going to have something in the next couple or three years that may drop ApolipoA: down, this, I think, is very good.
Segment:3 Discussion of FREEDOM Follow-On Study.
AKCEA-APOA: The FREEDOM trial is a study that actually moved the guidelines into the treatment like a must of using CABG in patients with multi-vessel disease in diabetes.
AKCEA-APOA: This trial was presented in 2012 and when this trial was presented-- Actually I have here I think the last slide of what we said, is that the study needs a long follow-up in terms of mortality. So, the original FREEDOM trial was 3.8 years of follow-up, 2,000 people, multi-vessel disease, drug-eluting stents vs. CABG.
AKCEA-APOA: In the results, the outcomes, the primary endpoint was the combination of mortality, non-fatal MI, and non-fatal stroke. The results were 26 percent events with the stenting group vs. 18 percent with the group treated with CABG and this moved the guidelines into Class One. Now the question is, how can we have a long follow-up? And this was an NIH-funded trial, but NIH said the results are already there, there's no need for more funding.
AKCEA-APOA: This is one of the great problems we have today. We talk about short-term trials-- and we like to live 20, 30, 40 years-- so the question is how can you convince the funding sources to really go into longer follow-up? So we got private funding because I thought that this was important to know a long follow-up, but we had trouble, because to follow patients for more than forty years is very difficult when you don't have federal funding and otherwise.
AKCEA-APOA: So what we did, with private funding, we convinced the institutions who have the highest recruitment to participate in an eight year follow-up, and they accepted, twenty-five institutions. So we were able to follow 50 percent of the patients properly randomized. This is not that we lost 50 percent of the patients, these were a group of the total group that were followed appropriately. The results actually were quite striking.
AKCEA-APOA: So let me give you the data of 2012, which is 3.8 years of follow-up, just in terms of mortality, which is really the endpoint that we were pursuing. There's been a lot of debate whether mortality is affected by CABG and by other means in patients with coronary artery disease. Everybody talks about myocardial infarction and so forth. So we look at mortality in 2012. It was actually 16 percent in the drug-eluting stent group and 10 percent in the CABG group with a p-value of 0.049. We didn't want to make a big deal of it because you're in a borderline situation, so we made a big deal on the combination of all the endpoints, but these left us in the sky-- what happens with mortality?
AKCEA-APOA: So we know the mortality at years full op and test the mortality on the 50 percent of the patients, from day one to eight years was actually 23.7 percent in the drug-eluting stent and 18 percent in the CABG group. And then when we put all together, it was 18 percent vs. 24 percent-- very, very significant. We were surprised, and the reason we were surprised, because this is an elderly population in general, 65 years, and what you expect is everybody dies so what you expect is the curves, regardless of what you do, and actually it continued to go up.
AKCEA-APOA: I think this is an important lesson and this came out in the discussions with the people of the trial and this is an important lesson, is that we need trials that go eight, ten years and the problem is the funding. We were able to really succeed in the way we did with the limitations that are obvious; the limitations of this study are four. Number one, it's 50 percent of the people and again it's not patients that we lost.
AKCEA-APOA: The other thing is that the stenting group, they are all saying the newer stents, watch out this, absolutely wrong. The newer stents don't make a six-point absolute mortality difference compared with the original stents
THAT'S NOT.:
THAT'S NOT.: Maximal 2 percent-- there's thrombosis and so forth. So I don't think the newer stents would make diabetic trial, the field trial, too different in terms of mortality. Now we have medical therapy for diabetes. This could make a difference, you know? We don't know, and then the study only looks at mortality rather than all the other events, but at least CABG is to stay. And now we are talking about mortality not even myocardial infarction is talking a long-term follow-up.
THAT'S NOT.: These are the three studies that really were positive but now we come with two studies that I think are worth it to discuss because although being negative, there is a lot of insight that one can get from these.
Segment:4 Discussion of CIRT Trial.
THAT'S NOT.: One is the CIRT study of methotrexate, and the other is the DECLARE-TIMI-52 on dapagliflozin, which is for diabetes. Let's begin with the first one. Well, you're all aware of the CANTOS study.
THAT'S NOT.: The CANTOS study were patients with coronary artery disease, and the injection of canakinumab a monoclonal antibody that blocks interleukin-1, gave significant results in terms of cardiovascular events in patients who had-- Actually, this drug didn't lower the lipids, it didn't lower blood pressure, so it's again one of these drugs that just work on interleukin-1 probably as an anti-inflammatory drug and this was CANTOS.
THAT'S NOT.: What was important in CANTOS is that the inflammatory... the inflammatory molecules that we all talk about, CRP, and in this case, interleukin-1, were both blocked and the higher the CRP level, better were the results. So, in fact the good thing in CANTOS is they really aim on the molecular basis in the pathways of inflammation that were very recognizable because they would block, and the results were very significant.
THAT'S NOT.: What happened with methotrexate is the drug is cheap. It's used for lots of conditions, psoriasis... This other drug, canakinumab, is going to be very expensive, so it was good to attack the inflammatory process through a different mechanism, and this was methotrexate. And now I'd like to present the study. The type of patients in this study was very similar in CANTOS, except maybe there were more diabetic patients and perhaps the patients were more risky with multi-vessel disease, but I wouldn't put great difference between the CANTOS study and this study.
THAT'S NOT.: We are dealing with nearly 5,000 patients with a study of about 500 centers in the United States, and these patients were actually randomized into once a week 15 to 20 mgs of methotrexate vs. matching placebo. The endpoints were actually four, the primary endpoints-- non-fatal MI, non-fatal stroke, cardiovascular death, and hospitalization for unstable angina leading to urgent revascularization.
THAT'S NOT.: So, four endpoints, quite appropriate. What happened with the four endpoints? The results were completely negative, no difference. Now, this is important, and I read the conclusions as they came out in The New England Journal. "Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1 beta, interleukin-6, or C-reactive protein, and did not result in fewer cardiovascular events than placebo." What they're trying to say is the pathways of inflammation were not affected.
THAT'S NOT.: I think this trial is important because when we talk about inflammation, you might say, well, I can use ibuprofen, or aspirin is working as an anti-inflammatory in the arteries, it's probably not the case. You really have to block the pathways that I mentioned and that was the good thing of the CANTOS study. So today we can say, inflammation is very important in the atherosclerotic process, but the way that you're going to block it is so different that you just cannot talk about anti-inflammatory drugs.
THAT'S NOT.: I think this is a great lesson from this study. I think it was worth it, it was well done. Methotrexate is a very interesting drug that is being used. There were a number of side effects-- liver enzymes were slightly elevated, some reduction in leukocyte count and the hematocrit-- but anyway, at least the lesson is that the trial was not wasted. It gave us a tremendous insight into inflammation. There are many types of inflammation, or better to say, there are many pathways that you can block, and we found one that works and another that doesn't work.
THAT'S NOT.: By the way methotrexate, nobody knows how it works, so let's be sure at least it doesn't block the molecules that were blocking the CANTOS. The other study, to me, the number five, or the second study in terms of learning, is the one about the diabetes type 2. You know how fascinating these last few years have been with the new SGLT2 blockers, and that is what they block is the absorption of glucose by the urinary tract.
THAT'S NOT.: This causes some degree of drop in glucose and then significant decrease in cardiovascular events as it's shown in some of the studies with empagliflozin for example and canagliflozin. They showed a decrease in mortality in patients with cardiovascular disease. They were high-risk patients. As these studies were being published another study already had taken off. So the study I am presenting here took off when the results of the other two studies in cardiovascular events were already positive.
THAT'S NOT.: So they continued and they called this a safety study. This is very complicated, and I don't want to go into the politics here, but we are talking about a drug, dapagliflozin, is one of these drugs like the other two that they mention.
Segment:5 Discussion of DECLARE-TIMI 58 Trial.
THAT'S NOT.: This was presented by Dr. Wiviott from the Brigham, and it's called the DECLARE-TIMI-58 study. Well, there's a difference and this is what we learned. Now there were 17,000 patients.
THAT'S NOT.: 10,000 did not have any cardiovascular disease, critical, when in the other studies most of the patients had significant disease. What this is telling us is it's quite different to go into so-called secondary prevention than to go to primary prevention. The study has so many outcomes up and back and forth that I don't want to waste your time, just to say it didn't work in terms of the MAZE:. It has some results in terms of hospitalization for heart failure, very interesting.
THAT'S NOT.: So, it's another study that at least it tells us that this drug probably, the effect-- or these drugs, probably the effect has very little to do with the drop in glucose because the main results are in heart failure-- in left ventricular hypertrophy in diastolic functions, systolic function-- and then on top of that, there's some decrease in cardiovascular events, which was not proven with this one, but it was proven in terms of heart failure.
THAT'S NOT.: So, again, with new types of drugs that are in diabetes type 2 that really dropped somewhat the glucose doesn't produce hyperglycemic events, it drops glucose a little bit but probably the effect of these medications are different, and they are quite successful in patients with type 2 diabetes. And according to this study the patients should have significant risk for cardiovascular disease, and even so, at least they work in heart failure, but if you want to decrease cardiovascular events you have to go in a high cardiovascular risk group with coronary disease, heart attacks, peripheral vascular disease and so forth.
THAT'S NOT.: I think it's a great study, very well done, and basically what it shows is we have a number of drugs today that have been targeted for one thing, triglycerides, I presented today this glucose, but they probably have the effects are different than what you are aiming at, but are good drugs in a way to be considered, particularly in heart failure. Now I want to present to you the question mark of the day, which is Omega-3 and Vitamin D, and I want to go into some detail because it is very concerning how industry is making money from all of these and how these drugs are portrayed to the public in a way, which is nonsense, because, as I will be presenting to you, even the background information on Omega-3 and Vitamin D is very weak, but the way that industry has protected these drugs in terms of the public is amazing.
THAT'S NOT.: Let me begin by saying that the people who did the two studies are very good people, so let's just start by saying that the group of JoAnn Manson and the others that really work on these two drugs, the so-called VITAL Research group, is very, very good. We are dealing with top people so be sure that we don't mix now the way the results were presented or portrayed to the press or whatever the press did with them, with the group that did this study.
Segment:6 Discussion of VITAL Omega-3 Data.
THAT'S NOT.: Let me begin with Omega-3 and give a little bit of background. So, you all know about the fish and so forth. Omega-3, it has been portrayed by being a very high content in fish and this is why people in northern countries who eat fish have less cardiovascular disease. This is how it started. Then the studies in secondary prevention gave inconsistent results, not much in primary prevention with Omega-3m and certainly one of the questions was in cancer.
THAT'S NOT.: So, they began, I remember about fifteen years ago talking about cardiovascular disease, and in the last five years we have been trying to absorb the concept that maybe these Omega-3 may prevent cancer. So the studies that I am going to be presenting were aimed to cardiovascular disease and cancer. Let me begin with the first one, were both together. Basically what we are really talking about, a placebo-controlled trial in twenty-five thousand people, which actually did not have obvious cardiovascular disease.
THAT'S NOT.: So this is really a primary prevention study. It is a 2 x 2 factorial design. So, we have Vitamin D in one arm, at a high dose by the way, of 2000 international units per day and the omega-3 at the high dose of 1 gram per day. Again, cardiovascular prevention. And they were looking at the prevention of cardiovascular disease events and the prevention of cancer.
THAT'S NOT.: The cancer that was in the primary endpoint was a spread cancer, like metastasis. Then they have secondary endpoints, which is everything I said but much more meticulous on every conceivable endpoint you can say. This came in the secondary endpoints, and these were the results. The results on the measured cardiovascular events and cancer, metastatic cancer, were completely negative. Okay, so there's no issue for discussion.
THAT'S NOT.: Now, what is interesting is what was portrayed as positive, and let me present this to you. There was a pre-specified endpoint out of twenty. There was myocardial infarction. In myocardial infarction the hazard ratio was 0.72 in favor of Omega-3, but let me give you the real results. It was 1.5 percent MIs in twenty-five thousand people in the placebo group vs. 1.1 percent in the group treated with Omega-3.
THAT'S NOT.: If you guys are excited about it, I think this is your problem, but this was portrayed as the main-- Omega-3 is preventing cardiovascular disease. Actually very little on cancer by the way. Now I will tell you the second issue that really came into the press, particularly in The Washington Post. In black people the results are even better. People who do not eat fish is even better, and these were not pre-stratified.
THAT'S NOT.: These are things that came out of a thousand ways you look at data and then you come with something. So, it's very, very deceptive to see The Washington Post saying Omega-3 prevents cardiovascular disease. Big title, first page, okay. I presented to you the data.
Segment:7 Discussion of VITAL Vitamin D Data.
THAT'S NOT.: Now, let me go into Vitamin D. The Vitamin D study was based on original studies that people who actually are all day at the beach-- you know, they are doing better, because I don't know what happens with Vitamin D in the skin and the exposure and so forth in terms of cancer, in terms of cardiovascular disease.
THAT'S NOT.: This is how it started, it's like the fish in Norway, but this was Vitamin D, people being exposed to the sun. And then it was found that perhaps people with low levels of Vitamin D they were pre-disposed to cancer and cardiovascular disease. This is actually the background of Vitamin D. Vitamin D is sold all over the place as a supplement. Well, actually it was the Institute of Medicine that became very worried about all that was published on Vitamin D because it was not good data, and they said you have to do a trial on primary prevention with a high dose of Vitamin D and see what happens, and this was the Institute of Medicine that decided to push this forward.
THAT'S NOT.: So the study took place, it's the VITAL Research Group that did this, and they put together what I just presented on Omega-3 and Vitamin D in the 2 x 2 factor. So, it is the same design. The endpoints, preventing cardiovascular disease and cancer, primary endpoints, secondary endpoints by a large number, twenty-five thousand people, five years of follow-up. Results.
THAT'S NOT.: What came up in the press is that in terms of cardiovascular disease really not much could be said because everything was negative. But in terms of cancer, there was a 17 percent decrease in the incidence of cancer in the Vitamin D group. But now let me give you the figures-- 0.8 percent in the Vitamin D vs. 1.1 percent at five years of follow-up. If you are excited, again, you have a problem.
THAT'S NOT.: This is what the great thing that Vitamin D did that came into the newspaper. Then they talk about whether you have normal weight, the results are more significant, less weight... So, I think these are two studies that really clearly present the problem of what the press portrays and what is the reality. Well, having said that, I will say to you that what I tried to do is to present what happened with triglycerides, with ApolipoA:, with the FREEDOM trial, these were positive studies.
THAT'S NOT.: The methotrexate and the DECLARE-TIMI-58, one about anti-inflammatory, the other one in diabetes, I think they were very well done studies, gave us a lot of thought about whether you're dealing with high-risk populations on one hand and on the other there are various types of inflammation or pathways that lead to inflammation in these two trials, and the Omega-3 and Vitamin D, I already mentioned why I presented those.
Segment:8 Discussion of the new Cholesterol Guidelines by the AHA/ ACC/ AACVPR/ AAPA/ ABC/ ACPM/ ADA/ AGS/ APhA/ ASPC/ NLA/ PCNA.
THAT'S NOT.: The cholesterol guidelines.
THAT'S NOT.: Now, first of all, to really understand those guidelines you need to spend four hours reading it and I did, and it was somewhat frustrating because there are ninety-six suggestions being made to people sitting here in this room, and if you really capture the ninety-six suggestions, you're really are superior to Einstein.
LAUGHTER: So I don't want to get into the details. I think on the positive side, very good. I think these guidelines do something very good, so I want to say from the beginning. The ways how guidelines are being presented, unless they are summarized in a way that are palatable, it is very difficult. I am going to be talking about four different subjects within ten minutes and then we'll open for discussion. The first stage it starts, the history.
LAUGHTER: You know, the first guidelines are really heading back in 2002 this was a Panel III, NHLBI, and the focus was cholesterol levels, if you remember-- high cholesterol, middle cholesterol, low cholesterol... cholesterol. Then, and I think this was good to start with, the 2013 guidelines, in my view had something very positive, and the positive thing as I see, this was ACC/AHA NHLBI, and I think to me the positive thing is that they talk about the whole risk factor profile package, not just cholesterol.
LAUGHTER: It's cholesterol within a package. I think this was a very good advance. There were questions about the 2013 in two issues. One was the calculator, you remember, and the age. In the calculator, the problem was maybe to put a ten-year full-risk factor profile, in the calculator they used data that was rather old, and the great question is the data today is different, the calculator is not accurate.
LAUGHTER: This was one of these. The other was the age. The patients were really focused on age 45 to 70. After age 70 or 75, who cares, because there was no data. So in a way you cannot just criticize because 2013 was based on just data. This is why the age, we don't have much data, but it was a negative thing in my view, and this is very personal and maybe I am wrong, but they didn't pay enough attention to reach a level of the LDL.
LAUGHTER: It was you give a high dose, or you don't give a high dose but about the final level to be reached was not emphasized. This is 2013. Now come 2018, and 2018 really improved 2013, in what level? Well first of all, the overall risk is there. The calculator is a little bit better, and I don't have to go into the details, but the black population is involved and so forth, that before were not, and they begin to talk about age, to talk, not really big statements but certainly a little better.
LAUGHTER: What I think is the best thing is that there are groups of people, it's individualized and what should be your final LDL cholesterol level, which was not in the previous guidelines. So I would say that overall, when you look at the 2018 so many organizations were involved, I think it's a good guideline. The question is how you read it and how you absorb it-- that's the problem. The next point that I'd like to make is to give a few principles that I think are very, very important here.
LAUGHTER: The first principle is, in some countries we use mg/dl but if you go to the UK, they don't know what you are talking about because they use mmol/L per liter, and I want to make this clear, when you receive patients from other countries, and they go in mmol/L and you don't know what that means, remember the number 40, and it's so clear, and that the 40 mg/dl is 1 mmol/L.
LAUGHTER: If you know that, when people say we have to reach a level of 70 to 80 mg/dl it's clear, it's 2 mmol/L. If you go, like in these guidelines you have to reach 100 mg/dl it's 2 and a half mmol/L. So what I'm saying is it's important to remember these because all of the patients come with different levels and values, and it's so simple and this is the first point that I would like to make. Now having said that, let me now go into what I consider are the critical issues to remember in our seven groups of patients.
LAUGHTER: I'm making it very simplistic, but I don't think I'm getting out of what the guidelines are trying to say. In these seven groups, they go from the most simple group, less risky, into the highest risky. So, let's begin in this way. Group number one, interesting. Individuals between birth and age 40, very simple what they say. I don't know what you measure or don't measure, but you look at the risk factor profile, and they say you have to follow a good lifestyle, and you're done.
LAUGHTER: And the reason why they don't go farther is because there is no data, so I want to be very sure, the guidelines are based on data and there's no data between age one and twenty, or birth and twenty and age twenty and forty. The only data is, it may not be good for your health if you continue to smoke, you know, then you start doing whatever you want. That's basically group one. Now, the interesting one is group two.
LAUGHTER: Group two is seventy percent of the people who walk in the street. Maybe less. These are people between age forty and age seventy-five who actually have some increase in the LDL cholesterol, okay? I don't want to put any figure because there are a thousand ways to look at this but this is the guy who has an LDL cholesterol of 140 and has other risk factors, never cardiovascular disease, and the question is, what do you do?
LAUGHTER: This is a very important group because what you do with this group, you use the calculator, I'm sorry to tell you this. Many of us don't use calculators, I use two or three risk factors, the calculator tells you that ten years of follow-up you have a risk that is between 5 percent and 20 percent. That's what you look at the calculator. Some people say 5 percent is too low, it should be 7.5. This is 8 points made on this 5 to 7.5, forget about it.
LAUGHTER: You get the calculator, you do it in your thing, and you see 5 percent at ten years to 20 percent, what do you do? Here comes the critical issue. You can do two things, one, if you are closer to the 5 percent, you drop the LDL by 30 percent. If you are closer to the 20 percent, you drop the LDL by 50 percent, and you know what you reach? You reach a level between 1700 mg/dl, you reach, you are not aiming, but you are with your conscience you are doing something good, okay?
LAUGHTER: Then you take care of the risk factors, this is always, I don't have to repeat this. But you might take another approach. We're in an intermediate group, I am going to do a calcium score. Calcium score came high in these guidelines. I feel good about it, because if the calcium score is zero, who cares? Why do you have to start giving statins too? The chances of having coronary artery disease are low.
LAUGHTER: On the other hand, if the calcium score is more than 100, better you pay attention. So, you have two approaches here. One is to ignore calcium score, the other is to do calcium score with the intermediate group. Both approaches are justified, but this is actually 50 to 70 percent of the people that you deal with, and the way to approach it is exactly what I said. Now, you're going to use a 30 percent drop vs. 50 percent.
LAUGHTER: I'm going to use the calcium score, now comes what they call discussion with the patient, okay? Because you're in a range. The question is then you discuss with the patient where you are. Very low risk, higher risk but you're still intermediate. I'm going to do a calcium score for you because if it is zero I will not use it because the patient doesn't want to use statins. Do a calcium score-- maybe the patient is right. So what I am saying is this discussion is really in the intermediate group.
LAUGHTER: Well 25 suggestions were made on the intermediate group, I already made it for you. This is a group that you have a range you have to make a decision, and you have two ways to do it, you discuss with the patient and that's it. This is group two. Now the group three is interesting. The group three is the patients that already have atherosclerotic disease. It's stable, maybe in the legs, maybe a TIA, maybe a previous MI, but it's a stable patient.
LAUGHTER: Here what you actually do, what the guidelines are saying, the approach is you drop the LDL by 50 percent, and you try to get closer to 70 mg/dl. Try to get closer. They don't say less than 70 mg. You can take 50 percent or closer to 70 and probably you are close to the reality. This is actually stable people, with coronary artery disease. Now comes something to me very interesting, and it is the high-risk group, how they are defined.
LAUGHTER: Two big events. A stroke and a myocardial infarction, two myocardial infarctions, or one big event in back risk factor profile-- particularly two risk factors: smoking, hypertension, and so forth. They call these very high risk. What they do, here they hit hard. You go into less than 70 mg/dl regardless, and you use the maximal dose of statins that you tolerate, and you move on. If you don't make it, ezetimibe.
LAUGHTER: If you don't make it, PCSK-9 inhibitor. But you really try to reach less than 70 mg/dl. This is group four, high-risk. The other two groups are so simple and you will understand it because the next group that they have is the diabetic patient. No atherosclerotic disease. They say this is like the group with stable coronary disease. Everything I told you, you drop by 50 percent or close to 70 mg/dl.
LAUGHTER: So, in fact, diabetes we all know this, it's treated in this guideline as the stable patient with coronary artery disease. In the other group, it's also simple. Patients who have cholesterol in the roof, familial hypercholesterolemia, LDLs of 200. What do you do? Exactly what you do with the high-risk patient with coronary artery disease. You go with less than 70 mg/dl, you use ezetimibe, PCSK-9 inhibitor, So, what I am really trying to explain to you is that you have to really go into the depth of the guidelines to come up with these six groups.
LAUGHTER: The age zero to forty, do the best you can. Forty to seventy-five, this is, all the other groups are based in this age. The most common one is the intermediate group, and you do the calculator, or you use your own calculator in your head, and you decide if it's an intermediate group, or you use the calcium score if the patient doesn't want to hear the word statin, and then you decide what to use.
LAUGHTER: Then from there you go to the stable group with coronary disease, you drop the LDL by 50 percent, close to 70 mg. The high-risk you really go hard with the ezetimibe and the PCSK-9, this was not in the previous guidelines. Then the diabetes is like stable and then the very high cholesterol familial is like the high-risk patient with coronary disease, but there are seven aspects here. The number seven, and I finish, is basically how you follow these patients, the six groups.
LAUGHTER: Basically, how you follow them is if you change those, you look at the new lipid profile between one month and six months. I use six weeks, you use whatever you want. One month and six months, you repeat to be sure that you are reaching the levels that are appropriate. Once you are happy, then every six months to a year you go to the patient, higher is the risk, closer you are in following it.
LAUGHTER: That's basically number six. Finally, I would say to you the final point I want to make, what the next guideline should have. Okay, this is my view. First of all, a follow-up of ten years is ridiculous. I mean, if you want to live only ten years, that's your problem. I certainly would like to live thirty more years. The risk-factor profile has to be prolonged much more than ten years.
LAUGHTER: This is a huge problem. We are missing so many people that we should treat, I believe, and we are not treating because we are using a short follow-up. The second thing is age. To say that age seventy-five is over, I think is a great mistake. To say that between age birth and age forty do healthy lifestyle, I think it's crazy. Here's the problem I view that has to be overcome. One thing is to be focussed on data, which is these guidelines, it's all data.
LAUGHTER: We don't have data between birth and age forty, but you have a lot of information. We have subclinical diseases all over. And to say that age seventy-five is over we know that there is a lot of data in the literature suggesting that age seventy-five, you still can do a lot to these people. So, although the data is not very strong because it's not trial, it's just observational data, I think the next guidelines should get out of the box of all should be in randomized studies and just go into observational data and be much more aggressive between age birth and age forty, and much more aggressive over age of seventy-five.
LAUGHTER: This is at least my view of what should be done.
Segment:9 Q&A Session.
LAUGHTER: So we have about 6, 7 or 10 minutes for discussion.
MAN 1: In the REDUCE-IT, did they have data separating according to triglycerides, meaning the patients with the triglycerides of 500 that have marked reduction in events-- Yeah, it was actually an interesting question. It was the same. In other words, regardless of the triglycerides level, the results were the same, so the triglycerides-- This is why I'm not sure the triglycerides are the marker, or I don't know what they are.
MAN 1: But I think this was into a completely different part. It didn't make a difference with the level of triglycerides you had.
MAN 2: But more than 500 were not included. No, it was up to 500 mg, yeah. Other questions? You have lots of questions, yes.
MAN 2: The information part, I think we really need to sort it out better. I just did-- the editorial came out in JAMA Cardiology on the inflammation, added inflammation and out-of-proportion inflammation. We really need to demonstrate that the inflammation is beyond the LDL UNINTELLIGIBLE:. That will be the only subset of the people who are likely to respond to the anti-inflammatory drug, be it methotrexate or the now two trials that are coming, which are all under ncd.gov, on colchicine, for example, and both UNINTELLIGIBLE: are large trials, well randomized, and one is UNINTELLIGIBLE:, and there's another one.
MAN 2: So, these trials also are headed probably towards the same trade as methotrexate is because we are not able to identify the people who have additional inflammation than what is normally produced by the LDL. So I think the role of imaging would come here and the role of better bio-markers might come here. I think we really need to look at it, because in 2018 we are still playing around with these clinical calculators of risk Yeah, I agree. and things like that.
MAN 2: And in my opinion this lipid guideline, I think in one way it's progressive that they've added calcium score, on the other side it is retrogressing because we probably are still sticking around 70 mg percent and 70 mg is not the answer; it has to be much lower than 70 mg. I tend to agree with you. Well you know I presented just this data and we are now looking-- we have a thousand people, nearly a thousand people-- we did PET scanning of the five arterial systems and with it MRI, and basically it's fascinating.
MAN 2: The first thing that you see is the inflammation before the plaque and then comes the plaque, and then comes inflammation again. So even in the process of atherogenesis, the inflammatory process is at the beginning probably as the cholesterol enters and then the plaque becomes vulnerable and is a lot of fat. So I think what you're saying is we really have to understand inflammation much better and certainly the role of imaging in bio-markers. But you know in guidelines, still the data is not available and we have to go with what we have.
MAN 2: Other comments? Yes.
MAN 3: Wondering about the results from PCSK-9 where it seems pretty clear that you keep getting good effects when you go as low as 10 with an LDL. PCSK-9 has really provided the information that the lower the LDL cholesterol, the better. and I think this had an influence on the guidelines when they say go below 70 mg/dl. But the question is-- I don't know the side-effects. I think we have to be very careful on that because you can have an LDL of 10 mg/dl but the question is how your brain is working.
MAN 3: We need cholesterol in the membranes, so we have to be very careful. I think, lower is better, but let's be sure we are not obsessed into getting a 10 mg/dl because I am not sure in a long-term what this means. That is all that I can say. I am sorry we have to stop, it's just one hour. I really appreciate that you came here today. Thank you very much.
APPLAUSE: