Chapters Transcript Dr. Ancowitz Keynote Lecture Course: The Cutting Edges in Stroke I'm gonna talk a little bit about what's new in heart disease prevention. And you know the insights that Doctor Ankowitz had many, many years ago haven't changed all that much in some of the, the big picture strokes, but, uh, some of the details have changed or we've gotten better at understanding them and so I hope to uh walk you through some of how the scope of, uh, cardiovascular prevention is changing, uh, and also just how a cardiologist thinks about preventing the, uh, preventing heart attacks and strokes over time. And so prevention is really simple but it's hard to execute and lifelong control of the big things that accelerate vascular disease, blood pressure, LDL cholesterol, uh, being overweight. Metabolic dysfunction, diabetes, smoking physical activity like we've known about all these things for a really long time but executing them, it really is challenging and it seems like it's getting more challenging as time goes on. And so you know this is a golden age of preventive medicine even if it feels like things uh from a population base or sort of spiraling in uh in a scary way uh but preventive medicine has changed a huge amount over the last decade or two, and my goal for today is pretty simple. let's talk about what's new we're gonna talk about screening, treatment strategies, and then the tactics to execute those strategies. A couple of just quick pieces of nomenclature so we're all on the same page. So ASCVD is atherosclerotic cardiovascular disease, which encompasses coronary disease, cerebrovascular disease and peripheral vascular disease. When I am referring to, uh, stable disease, that means nobody's had a heart attack or stroke recently, uh, probably within the last year. I explained this to patients that you know we talk about this as vascular disease but it's not really disease of the heart it's disease of the blood vessels around the heart and thinking about this as a systemic disease of arteries is a really important framework for how you think about treating it and you know a systemic disease needs systemic treatments and that's why medicines are almost always going to be better than interventions or procedures. And so I want to talk first about screening uh because screening is an area where I think that there's really really exciting new data. The Dan Kavis study was published last year, this year 2023, uh, and it's the most comprehensive screening project that anyone's ever done. And so Danish researchers invited people from the general population, uh, to undergo a variety of different tests, um, and. They invited them to undergo CAT scans, ankle brachial index testing, blood pressure checks, um, they measured some blood work, um, and they also did a short term heart monitor to look for arrhythmias and you can see the details of everything that they looked at over there they didn't specify any interventions. All they did was invite people for screening and then they observed what happened and. So I think it's notable that the people who were screened are very different than the people who chose not to be screened and so this is uh this is a trial looking at inviting people for screening it's not a trial looking at actually screening and so the control group and the invited group, meaning people who were invited and people who weren't invited, were really, really similar. But when you looked at the people who are invited and you compare them to the people who are the and you compare the people who accepted screening to the people who didn't, what you see is that people who accepted screening were more educated, they were more likely to be employed and they were more likely to be well medically treated. And that means that the sickest patients, the ones who probably would have benefited most from having uh some of their cardiovascular disease brought to medical attention, didn't even take anyone up on their offer. And you know if you look at the results of this trial, what you can see is that you know the primary outcome has this P value of 0.06, but if you look at that confidence interval, it's 0.9 to 1.0. And so I look at that and to me that says screening is beneficial and you know you can look at the subgroup analyses which are hypothesis generating and not hypothesis testing you can see that younger people seem like they benefited more uh but it seems pretty clear that when it comes to screening to me there's a very, very high probability that inviting people to be screened. Has a really a really good chance of actually improving their outcomes and that says nothing about the medical therapy that you do from people afterwards um and so you know I I think that this benefit that you see in younger people is really really interesting and you know the the next section of this talk is really gonna focus on why that might be the case. Um, but I look at Dan Kavis as a positive trial, and it really to me supports at least inviting people or offering screening for the general population. It's changed the way that I talk with my patients about the importance of doing things like calcium scores and uh and regular blood work. One of the things that's changed the most over the last 10 to 15 years is the idea that lower for longer is better. So heart disease is here for a really really long time before it causes any problems subclinical atherosclerosis happens in teens and twenties, and it takes decades for this to result in something bad happening to a patient before somebody has any symptoms of any kind of cardiovascular disease, they've had atherosclerosis happening for a really really long time. And so the sort of the way that we approach prevention. Is undergoing a shift where we understand that if you change the trajectory of the disease early you can change what happens down the road and there are a lot of studies looking at regression of atherosclerotic disease when you control blood pressure and when you control lipids. I have patients who come in all the time to see me with a CAT scan that was done for some other reason and there's calcium in their coronary arteries and that the first thing that they ask me is like can I reverse this? And part of me says it doesn't really matter if we reverse it, we want you to die with this and not from it, but patients don't like the idea of having calcium in their bodies and there there's a lot of data where there's proof of concept that you can induce regression whether you induce. Remission I I think is still an open question, but you can really change what plaque looks like on serial imaging by controlling things and the earlier you start, probably the easier it is because the more calcified things things are it's just harder to reverse that process. And so in 2006 there was this paper published out of UT Southwestern looking at a genetic variant that leads to lower LDL cholesterol and um it's a very a gene variant called PCSK9 which helps to take it LDL receptors in from liver cells and so if PCSK9 doesn't work, it means that your LDL receptors stay on the surface of the liver cells and they draw in those LDL particles from circulation much more effectively. And what's really interesting with the PCSK9 mutation is there's a dramatic reduction in cardiovascular disease risk with this mutation even though there isn't that dramatic of a drop in LDL cholesterol numbers and so it's really interesting to see that you only need a modest reduction carried lifelong in order to have a really really significant benefit and. That genetic difference, so if you look at the the graphic on the uh on the right side, what you see is the the blue bars are the genetic studies and the red bars are the drug studies and drug studies are almost always looking at people with some established disease or at least long standing risk factors for disease and when you achieve equal LDL lowering with a drug compared to a genetic mutation. You see that the genetic mutation lowers risk quite a bit more in some cases in order of magnitude more and that really speaks to lifelong control lowers risk and it's not just how high the numbers are it's also the duration of time that they've been high for. From lots of drug trials we know that how much you lower the atherogenic lipoproteins corresponds to what your risk reduction is gonna be. This is a graphic from the Improve it trial which was the the trial had established the benefit of azeamide as an adjunctive treatment to statins, and all of those boxes are different drug trials and you know that fit line basically shows that. The reduction that you get in LDL corresponds to what your reduction in overall cardiovascular disease risk is going to be and the things that lower the numbers more are going to have a bigger impact, but I, I think the genetic data really provides a compelling reason to start earlier rather than start later. And if you look at the the trials on blood pressure and on lipid management, what you see is that the curves really look similar across all domains of prevention where it takes a while to start showing a benefit and then once you start showing a benefit those curves separate more and more over time. And it's just telling a different version of that same story which is the earlier you start, the bigger impact that you're gonna have and those curves are continuing to diverge and when you look at long term data, long term outcomes from statin trials, from PCSK9 inhibitor trials, from blood pressure trials, the story is the same over and over and over again and the more you see the same story, the more compelling that it gets. So I think it's really interesting to note that personal or prevention doesn't even need to be personalized. This is a trial published last year looking at a polypill that contained a small dose of an ACE inhibitor, a small dose of a statin, and 81 mg of aspirin, and they gave half the patients in the the trial a poly pill, and they gave half of them a placebo, and that poly pill curve really looks quite similar to the lipid lower. And blood pressure curves and so you know I, I think a lot of uh a lot of doctors really pride ourselves on taking care of the individual rather than just sort of treating everybody the same but this is an argument that if you just lower the numbers across the board you might lower risk across the board and that it doesn't, you don't need to be so precise as long as you're employing. Treatment strategies and so it's really interesting to see the at least like for for those of us like myself who really uh take pride and I treat every patient as an individual and I try to make my care as specific to the person across the room for me as I can that maybe I don't need to be quite as uh as detail oriented because I could just give them a poly pill and everything would be fine. I don't know. Um, and so the story is the same risk curves diverge over time. This is data from the PCSK9 inhibitor trials, and it's telling the exact same story, which is that lower for longer is better. And so what I take home from this idea about prevention strategies is that risk is proportional to exposure over time this happens over the course of decades the earlier that you detect it, the earlier that you're able to persuade patients that treatment makes sense. And so I'm really, I, I've really changed my practice quite a bit to be more aggressive with screening and to be more aggressive with not necessarily tolerating that blood pressure that's 135 systolic for uh for longer than I than I should and you know if one thing that I found very, very compelling is showing patients pictures of their scans and it's one thing to say your blood pressure is a little bit high. We should put you on another blood pressure medicine so I think the average patient is resistant to adding more pills but when you pull up a CAT scan of their chest and you say. This, you see these bright white spots that's calcium in your arteries. Have you ever heard the term hardening of the arteries before? We can see that visually on your scan that draws it home for people a lot more, uh more clearly to me than just sort of vaguely talking about their numbers and so it's been a a a a a real uh a real sort of valuable thing for me to see how important screening is and the fact that screening has a real benefit. We're gonna move on from strategies of prevention to tactics of prevention. And so uh uh uh a graphic like this is one of the things like one of the hottest topics in um in cardiology prevention it's this idea about residual risk and personalized prevention and so residual risk comes in a lot of forms because the pathophysiology of heart disease is pretty complex. It comes in inflammatory risk, it comes in lipoprotein risk, comes in thrombotic risk, um. It comes in LP little A risk which we're not really gonna talk about and then metabolic risk which I think is actually the most exciting and interesting thing to to talk about, you know, a lot of, uh, a lot of cardiologists and a lot of physicians overall will make a bifurcation between somebody with diabetes and somebody with pre-diabetes or metabolic syndrome, but that's uh that that's a sliding scale and it's a continuous variable, not a categorical variable and so I'm gonna spend the next little part of this talk talking about metabolic risk and. So metabolic risk comes in the form of metabolic syndrome and metabolic syndrome is a constellation of findings that were identified decades ago that basically show up with abnormal fasting glucose, low HDL, high triglycerides, big waist circumference, and elevated blood pressure and. Metabolic syndrome occurs on a spectrum. You're not considered to have metabolic syndrome unless you have a few of the things on this list, but very, very few Americans actually have completely normal metabolic function even when you're taking into account uh the very generous kind of uh kind of guy. Headlines and lifestyle modification meaning more exercise less calories weight loss, stress reduction has always been the mainstay of how we think about like treating metabolic syndrome but I I think that there's compelling data that that maybe should be changing a little bit. And so we'll start out with a little talk about diet. So the Mediterranean diet, um, is probably the diet that has the most robust evidence behind it, and it tends to be, uh, at least what auto populates in notes of a lot of doctors who do secondary prevention. Nuts, olive oil, uh, like reduced red and processed meat, um, and this is the prettied trial that kind of established that at least compared to a low fat diet that a Mediterranean diet seemed like it lowered risk of cardiovascular events. It's not life saving and I'm not really sure what those curves will look like when we continue following out like maybe they are continuing to diverge, but I think that just based on my clinical practice they're probably gonna end up coming a little bit closer together. And I want to point out that we don't really know what made the difference in prettied and so this is just from the methods of the the trial, and you see the patients got free olive oil or free nuts or a small non-food gift and if you look at the dietary recommendations that they got those dietary recommendations were different across the groups. The low fat diet was not told to stay away from soda like the Mediterranean diet group was and you know that I, I think that there there's when you're testing the results of multiple interventions it's really really hard to know whether it's the Mediterranean diet. So effective or whether it's getting free olive oil and nuts shipped to you once a month or whether it's the dietary advice that you get that's more effective and you know when you're thinking about what do you tell the patient in front of you and I get a lot of questions about what should I eat and. Um, you know, Mediterranean diet has some evidence behind it, but I don't really feel all that confident that I have any clue whether a Mediterranean diet is better than a general healthful diet or a moderate fat diet or some of the other diets that that we're gonna talk about. And you know I bring this slide in this is not a slide on cardiovascular disease. This is a slide from the mind diet looking for prevention of neurodegenerative disease, um, where they had groups take a calorie restricted diet or a diet that included like brain healthy foods like blueberries, and if you look they gave patients free stuff. In this also and you know both the control group and the intervention group had an improvement in their cognitive scores, but the control group got a food subsidy and so it's it's really really tough for me to have any confidence that these trials tell us anything beyond what my common sense would tell me. Um, and I don't mean to be cynical about it, but I think that when the data shows what it shows, we should be honest with ourselves and honest with our patients about what it tells us and also what it doesn't tell us. The DASH diet similarly has a pretty good evidence base behind it improving blood pressure, uh, lipids, uh, the DASH diet is multiple interventions and so it's very, very similar to some of the other things that we've talked about where I don't know what's actually driving the benefit with this diet. Uh, Doctor Aquis had shared, uh, uh, an office with, uh, with Doctor Atkins, which I learned today. Uh, so low carb diets are really, really interesting for a couple of different reasons. Um, so the graphic on the right. This is a trial called the A to Z trial that compared the Atkins diet to a bunch of other diets, and it's notable to me that the Atkins diet group lost more weight over the course of 12 months. They also had a drop in their blood pressure. They did have a rise in their LDL cholesterol, but a trial like this is not powered or long enough to detect a change in overall cardiovascular disease events. Um, I have quite a few patients who are young. and lean and very persuaded that their low carb diet is the thing that makes them feel so wonderful and there's this phenotype that um I've observed and that's been documented in the literature called the lean mass hyper responder phenotype where people's metabolic health gets really good, their triglycerides go down, their HDL goes up, their waist circumference shrinks, their blood pressure, uh, goes down, but their LDL. shoots through the roof and some of the highest LDLs I've ever seen 300 mg per deciliter, 350 have been on people who are on super low carb diets. There are ongoing perspective trials to look at this group with serial CT imaging of their coronaries and you know, metabolic syndrome definitely drives cardiovascular disease. Some of that's through blood pressure, some of that's through dyslipidemia, but. What's the what what's the trade off and I, I'm not sure that I really know how to counsel these patients when they come to me with really high LDLs and so how I approach it is if the diet makes you feel good, you feel like your energy is better and you're sleeping better, that's fine and it's reasonable to stay on that diet, but we should lower your LDL with medications and. You know, it, it won't be surprising to many in this audience that the people who are very persuaded that their diet is right may overlap a lot with the group that thinks statins are bad for you. And so that's often a tough sell, but I, I tell people, look, we have the same goal. I want, I don't want you to have a heart attack or a stroke, and I don't think that you want to have one either. And my read of the evidence is that living with an LDL of 250 mg per deciliter for decades of your life, it's probably not all that good for you. So I think that you can sort of sum up the dietary strategy and you know we don't have really great evidence to support any real conclusion but we have some ideas and when you look at the overall data it on like how effective our diets it's pretty damn depressing people gain regain weight over time people who lose weight get it back and if you look at the CDC heat maps on obesity like you can see on the right side of uh of this slide. Those numbers are just going up and up and up over time and so I think if you go back 20 years there was no state that had an obesity rate over 25% and now every state has an obesity rate over 25%. Um, and so I reconcile something like this. I don't think that people's collective willpower has changed. I think the environment has changed and so I look at obesity and metabolic syndrome as environmental diseases, and I tell people if you don't make a permanent change to your environment, your trajectory is one of weight going up and metabolic health worsening and disease risk going up over time. And so environmental thinking of this as an environmental approach, uh, and not as a matter of personal responsibility is something that I've gotten a lot of disagreement with some of my colleagues about but it's one that I think fits the data much better than saying that people suddenly got lazier or more gluttonous over the last 30 years. So, the anchor and memetics, these drugs that you've been hearing about in the news all the time, Ozempic, Mounjara, zebound, Wagovi, um, these are a paradigm shift in the way we treat metabolic disease. Does anybody know what that picture is down at the bottom? Yeah, what is that? Yeah, the so the Gila monster is a lizard that eats only 2 to 3 times a year, and So researchers had this, uh, had this idea that maybe there was something unique to the Gila monster that regulated its blood sugar that let it eat that infrequently and so this substance in the saliva of a Gila monster excendin 4 is actually turned into a drug called bieta or exenitide and that's an anti-diabetic drug that's been around for quite some time, but it turns out that these drugs really act centrally and they spontaneously reduce appetite and. If you talk to a patient who goes on these drugs, I, I have a lot of patients on on these medications. I hear really interesting insights from them. I've had patients tell me I didn't realize how much of my um my eating was emotional and because I was just so damn hungry all the time. And you hear patients talk about how they used to go to a work event and you know like somebody brings in donuts or cake for a work birthday and they used to have 3 donuts and now they feel they're OK with a bite or two and so these drugs act in the brain and they help patients navigate the environment and it's been really, really. Interesting to me to talk with patients to hear what their experience on these drugs have been and you know I think that there's a lot of different mechanisms but from if you talk to experts in the field or if you talk to people who are on these drugs, the central appetite regulation uh mechanism is probably the one that's the most compelling. So both Seaglutide, which is probably the most popular one of these Ozempic and Wagovi, uh, when the drug is approved for weight loss, it has one name and when it's approved for diabetes, it has a different name and so the simmaglutide formulation for diabetes is Ozempic, and the weight loss formulation is. but it's the same drug Turzepatide is munjaro for diabetes and bound for uh for weight loss and what you see from these trials, so this is the step one trial, um, on the, on the left, and the step one trial showed a weight loss of about 15% of body weight over a little over a year. So that means a 200 pound person loses about 30 pounds. Um, and trazepatide, uh, in the surmount 2 trial showed a a weight loss when you get to the higher doses of around 20%, some as high as 25% of body weight, and so that's a 200 pound person losing over 40 pounds of weight. It's pretty remarkable to see what those effects are, and the curves look really similar where the weight loss is more dramatic up front and then it plateaus and. You know, the, uh, there's a lot of questions about what are the long term effects. We have no idea, uh, but I can tell you that the short term effects are pretty impressive and you know the trade off is, is one where we're gonna learn a lot more over the next handful of years, but right now it's pretty compelling. I think Ozempic gets the most press, but Moonjar's appetite is probably a little bit better. This is data from a trial comparing the two the two drugs and what we found when you compare imaglutide with trazepatide is that trazepaide leads to more weight loss, a bigger drop in hemoglobin A1C, and anecdotally patients have way fewer side effects with it. Turzepatide, uh, impacts two hormones in the acridin system, whereas imaglutide is really just on, uh, a focus on GLP1. And you know different hormonal mechanisms uh treating different hormonal mechanisms is the sort of thing that you see a story of a lot of different places in medicine. And so if you think about heart failure, we treat drugs with heart failure, 4 different classes of medications. When you think about HIV or tuberculosis, you hit a bunch of different pathways and so there's something that's kind of like mechanistically elegant about the idea of working on multiple hormones in the anchorin system and. There's uh starting to be phase two data on actually triple agonists, um, and so this is retta tide, which is the next one down the pipeline, and you can see the data on weight loss is 20 to 25% of body weight. But these drugs are not just for weight loss and they're not just for diabetes and so the select trial was presented earlier this year and this trial I really think is a game changer and established soaglutide as a mainstay of cardiovascular disease treatment and so this is a trial that took patients who were mostly primary prevention and they randomized them to simaglutide versus placebo. And what you see is you see Kaplan Meyer curves for a for a mace endpoint that look really similar to the lipid lowering trials and the blood pressure trials and the craziest thing about select is these patients were really, really well treated to begin with. They had LDLs that were in the 70s. They had blood pressure that was around 130/80. They had an A1C that was 5.8 at baseline, and they were on antithrombotic medications. They were on lipid lowering drugs and so this is a group that I think that for most of us, if you see a patient come to you who's never had a heart attack, who has an LDL of 78, who has an A1C of 5.8 and a blood pressure of 130/70. You're gonna tell them they're doing a pretty good job, but adding something else to their treatment regimen may make sense and so I, I like to me this stat is really, really compelling and it's hard to ignore the fact that you're not just lowering cardiovascular end points if you look back. The all cause mortality on that slide is statistically significantly reduced in the imagnotide group and so it doesn't just prevent heart attacks, it also makes you less likely to die and it's really, really crazy to see results like this from from a trial. Uh, lipid lowering is changing too. You may have seen beadelic acid or Nexliol. Uh, beaddoic acid lowers LDL numbers a little bit somewhere in the 20 to 25% range. Um, it lowers inflammatory markers as well, and it reduces mace. You know, the major side effects from this drug are that it increases the transaminases and it raises uric acid and so people who have gout or who have transaminase elevation to begin with may not do well on that drug. Um, but the reduction that you get in mace fits, it's proportional to how much you lowered LDL and so bemadoic acid is really interesting because it's converted to it to its active form only in the liver and so lots of patients who have myalgia or muscle aches or other symptoms related to statins don't have those same symptoms when they're on bemadelic acid and so I, you can look at this drug as an adjunctive treatment, um, and. You know, overall lipid lowering is in such a different place than it was uh just a few years ago. We have outcomes data on statins, Zetia, PCSK9 inhibitors, uh, icosaine ethyl or Visepa, which is, uh, an omega 3 fatty acid, uh, drug that uh I'm not gonna speak about, but. The all of those curves look the same. The reduction takes a while to see to visualize, and then it just keeps expanding over time as you lower the numbers. And so you, you know, the story of a lot of these things is a very similar story over and over and over again, um, but it just hammers home that point of simple but not easy. I think it's important that we don't get totally focused on what the biomarkers are and we remember that you also need to show that drugs lower outcomes, not just lower biomarkers and so. Uh, uh, there, there's, uh, a lot of, uh, active research going on in the triglyceride or remnant lipoprotein space. Prominent is a trial looking at, uh, permafibrate, which is in the class of fibrate drugs, and it's a drug that lowers triglycerides but doesn't really lower LDL. And if you look at those curves, those curves are basically. Like completely superimposed and so you look at curves like that and to me it says that even if you lower the biomarker I don't really care and so I am really really focused on I need outcomes data before I'm willing to prescribe a drug before I'm willing to consider putting my patients on a drug. Um, and just showing biomarkers is not enough. Unfortunately, the FDA doesn't really agree with me in that realm. And so, uh, inclieran is a small interfering RNA, um, that is that inhibits PCSK9, and it's really, really interesting to look at how the FDA is chosen to approach uh inlyeran because they approved that drug on the basis of data showing that it lowered LDL. Uh, but they didn't wait until the outcomes trials which are still kind of in use, and so I won't prescribe that drug because I think that you need to have really, really compelling outcomes data to, to make the risk worth the benefit until I know it doesn't actually kill people, which I won't until the outcomes trial is done. I don't know that I feel confident with a new molecule that has an unclear sort of sense of side effects to me. The CETP inhibitors is uh it's a really really interesting story and so the the CETP inhibitors or cholesterol is for transfer protein inhibitors have been around for. Years they've been around for decades. The the original trials were done in the 1990s, um, and published in the early 2000s. And so CETP is found, uh, is a loss of function is found more commonly in centenarians, meaning people who live to 100, than a lot of other things. If you talk to experts in the longevity space, what they will tell you is that CETP loss of function is a longevity phenotype, and those patients have lower risk of cardiovascular disease, lower risk of dementia, and seem to just have a much more like a much higher likelihood of living until they're 100 years old, but the first couple of trials of CETP inhibitors failed dramatically. And one of those trials showed an increase in heart attacks and strokes, um, and that was for a drug called torcetrapib uh which was uh being uh brought to market by Pfizer and if you talk to people who were involved in that study, what they'll tell you is that that drug raised, uh, aldosterone levels and so it raised blood pressure. Then there was another failure of a drug called dalcetrapib which didn't really lower the lipid numbers all that well because it wasn't very potent and the end result is that you've had two massive failures that have cost hundreds of millions if not billions of dollars in pharma development for this protein that the people who study 100 year olds are super convinced will prevent heart attacks and dementia over the long term. And so Obietrapib is in phase two trials right now and they're starting to enroll for the outcome studies. That is one of the hottest things that's sort of present in the sort of like waiting to come lipid space. Um, I'll be really, really interesting to see, see that data, and what will differentiate that from some of the other new drugs that we have like the PCSK9 inhibitors and glyceran, those drugs are injectable, and some patients are needle phobic. Obitrapib is going to be a pill that people take every day. It's not going to be a statin and so you're gonna be able to avoid all those conversations with your patients who um are really really sort of statin phobic, which is an increasingly large share of the folks that I see um but this is uh I I think that the the next couple of years are going to be just excited just as exciting as the the last years that we've had. I'm gonna come back to this concept of residual risk and so when you look at the the risk I think that we have the LDL part of this pretty well figured out so far with at least 4 different classes of drugs that uh both improve outcomes as well as lower numbers. Inflammatory risk is interesting and I'm gonna get into that in a little bit more detail in the next slide thrombotic risk is really, really challenging to sort out. And what that means is there's no biomarker for it and you just need to kind of clinically assess whether you think somebody has high thrombotic risk and we know that there's that you can thin somebody's blood really aggressively with both anticoagulants as well as antiplatelet drugs and you lower their cardiovascular disease risk but just like everything in biology, there's, it's a U shaped curve and if you thin the blood too much people have bleeding complications. Without a biomarker it's really hard to sort out who benefits from long term d or low dose rivaroxaban therapy compared to who you should just be treating the traditional stuff um and so the way I approach that is I think about residual thrombotic risk as being reserved for people who are actively smoking, people who have. Cardiovascular disease in multiple beds, meaning cerebrovascular disease, coronary disease and peripheral vascular disease. People who have had multiple unstable events, multiple strokes, multiple acute coronary syndromes, multiple adverse limb events and those are the patients that I'm really thinking will benefit from the long term, uh, more aggressive antithrombotic therapy that's a double edged sword though because those patients are also. The people who are at the highest thrombotic risk also tend to be at the highest bleeding risk and you end up like the vulnerable patients are the ones that need the most need our attention the most but they're also the hardest to take care of and so just being mindful that that's a particular area where the risk is pretty high of being wrong um is is something to keep in mind and we're still waiting on a biomarker and maybe someday that we'll have one. So the residual triglyceride risk is really, really interesting and so you'll see in this graphic they put prominence, which is the trial that neutral trial that I just talked about in that and so there's an overconfidence with a lot of experts in this field that we know the biology better than we actually do and so it's, it's just notable and if you there are there have been multiple graphics published in multiple pro. journals listing trials like prominent and strength which were neutral trials as being supportive of uh hypothesis of personalized residual risk prevention and so it's really really notable to me that uh you need to wait until the outcomes data and it's really it's just really really important to have a high burden of proof before you integrate new unproven treatments into the way that you take care of patients. Um, and you know, reduce it is the, the vasepa trial, the icosopine ethyl, um, trial. That trial they used a placebo of mineral oil and the mineral oil impairs statin absorption and there was a higher LDL level in the placebo group and so there's. This sort of ongoing question in the in the prevention community about how good is Visepa and how how real is this triglyceride hypothesis and so I'll just leave you with the fact that we don't understand it super well and the the trials to date have been kind of mixed in what we can really synthesize from them. LP little A is uh is a type of lipoprotein that's prothrombotic pro-inflammatory and really associated with accelerated atherosclerosis. The trials looking at those drugs are underway and so right now a high LP little A to me just means I treat the other things more aggressively and I aim for a lower LDL and I'm less tolerant of a blood pressure over 130 systolic, but that's a challenging group to treat and when. Patients read about it, it scares the crap out of them because there's a lot of really, really alarming stuff on the internet about how high LP little A is is is a death sentence and so it's something I check in everybody as part of my general screening but it's one of those things that sometimes when it's high you don't really know what to do with it. Uh, we've talked about the diabetes and metabolic risk quite a bit that's the area where things really are changing, uh, changing the most and where I'm most excited about what the what the treatments look like. I wanna talk about colchicine now so colchicine has been around forever. It's a drug that's uh that's used to treat gout, familial Mediterranean fever, uh, and pericarditis, and you know colchicine was just approved for the treatment of cardiovascular disease, at least in secondary prevention, and it goes back to this idea of residual inflammatory risk maybe if you have a high CRP and everything else is optimized, we should put you on colchicine. And if you look at the composite mace endpoint, what you see is like colchicine seems like it's better than a placebo but then you look at this other thing right at the bottom of death from nonc cardiovascular causes and. There were more dead people in the group that got Colchicine than there were in the group that didn't get Colchicine, and so I'm left with like this question of like, well what the hell do you do with that? Because like on one hand you won't have a heart attack, but on the other hand maybe you're more likely to die and. Um, I, I don't mean to be glib about it, but like when there's conflicting information like this, it's really, really hard to make heads or tails of it. And so I look at, uh, something like this, and to me I don't really see much of a role of cochine when there are so many other drugs that seem like they have a trend to prevent the things that my patients care about, which is not just having a heart attack or a stroke but also staying alive and. You know, the forest plot for um for the Colchicine trial, this is Lodoko, uh, showed the same thing where Look at there's only like two dots where placebo is better and one of those dots is death from any cause. And so I, I, I'm left with, I don't really know what the role of colchicine is, but I certainly don't think that it uh it it should be a mainstay of what we're doing. Um, it's interesting to note there's probably a subset of patients that benefit from that, and I'm not sure that CRP is a precise enough biomarker to really discriminate between that that stuff. Um, so this is a really, really exciting time for heart disease prevention. I think that the, the way that many of us think about, uh, about treating cardiovascular disease has changed quite a bit over time. And the people who do the most prevention are often the ones who are most likely reaching for their prescription pad rather than spending a little bit of time talking about diet and lifestyle and you know I'm not saying that the individual motivated patients can't lose weight and can't improve all of their stuff with diet and with exercise alone but the sum total of the population. Shows that medications might be necessary for for how we do this and these incred and memetics are their paradigm changing and you're you're seeing a lot of sort of popular media coverage of those articles but if anything to me they're undercovered based on how important they are and um and so learning how to navigate the modern food environment is something. That is really really challenging for many of our patients and so I, I really think about obesity and metabolic syndrome as environmental diseases and thinking about those GLP one agonists or the other inron in the medics as being helpful to our patients as sort of uh uh uh a friend on the the uh like in the back of their mind telling them maybe you don't need to eat this is a really useful um way of framing it. Lipid lowering is earlier is better lower is better and lower for longer is the best and then this residual risk idea that's very, very popular and very, very trendy it I I think that it's more hype right now than substance because if you look at a lot of what the residual risk data would say it's like lower their lipids. Lower their blood pressure and help them treat metabolic dysfunction and help treat metabolic syndrome and lose weight, diet, exercise, lifestyle and there's a there's a lot of unanswered questions and uh I'm gonna return to something that patients ask me all the time which is what should I be eating and my advice is always most people know what junk food is. It's really important to try to avoid it as much as you can. Portion size matters and most questions about healthy diet are people trying to find loopholes in what they know deep down. And so at the end of the day, like be honest with yourself about what's real and what's not real, which is that we all struggle with being honest with ourselves and so I think that that's a good place to to conclude. And so thank you. Yeah. All right, so we'll invite people to come up and ask questions, um, and then for our 200 people online, um, if you have any questions for Doctor Katz, please put them on the app and I'm happy to read them. Um. I can you one question that I have is just can you just tell us how you educate patients about activity uh and how you get them to actually do. So I didn't include a single slide on here about exercise and it's because it the data is so uh so one direction so unidirectional where exercise is good and more exercise is better and the best type of exercise is the one that you do consistently. People who only strength train tend to need a little bit more aerobic activity because aerobic activity has more compelling evidence that it lowers blood pressure and especially people who are power lifters, they tend to have stiffer vasculature probably because all of the time that they're spending with extremely high levels of blood pressure when they're Valsalva and. And sort of like very, very adrenergic um but that's a small subset of people uh especially of my patients who are power lifters most people struggle to get motivation to go to do anything and so I, I think that the the most compelling data would say aerobic exercise is really good, more is better. Most people don't get enough and most people don't do it hard enough, um, and you know as we get older, resistance training is important for prevention of sarcopenia even if it doesn't really do. Much to prevent uh cardiovascular disease and so it's just so straightforward uh and I try to I I I try to do anything I can to persuade people to do it um for I I will give people homework assignments where I tell them they have to keep a log of their steps. I will tell them they need to have a certain amount of uh of like uh stairs that they climb each day, and I'll ask people to send me my chart messages with a log over the, the month. Very few people listen to that, uh, advice, and I think that most people in general don't. Like homework, um, and so I struggle with that for a long COVID actually which I, I see a fair amount of physical activity, especially like low level aerobic activity with I, I, I keep patients with a max heart rate 10 beats under 180 minus their age. So for a 40 year old person, 180 minus 40 is 140 and so I keep people under a heart rate of 130 and have them work up to doing 45 minutes 3 times a week. It's probably bullshit, but it, it has been effective at, uh, alleviating symptoms in my long COVID folks. Can you talk a little bit about, um, you mentioned primary prevention, but in patients with, you know, no cardiovascular or crovascular events in the past. You know, I think we have good, you know, LDL data. Where, where are you at with the Ozempics and the wagovies and in terms of when do you start them? Is it a BMI level? Is it a, a composite sort of the younger somebody is, the harder it is to start uh a GLP one because Someone's gonna be on that for like presumably a really long time and the withdrawal data really look like it looks like a mirror image of the initiation data which is people stop that drug and they start gaining weight and it really looks like you just flip that curve over when uh when you withdraw the medication. So you have a conversation with somebody about like how do you feel like this is gonna gonna go over time, how important is it to you to lose weight um you know there's there's a lot of variables that that will go into that for heart disease prevention. I don't think that we're quite there, um, but for, um, but for general health and for uh high A1C, it, it's compelling. The I I spent a lot of time talking with patients about family history and in patients who have a family history of early cardiovascular disease, um, lots of people in their family either have heart attacks or strokes or get bypass surgery under the age of 50 or 55. Those are patients who I'm much more aggressive in treating. It's a real, uh, it's a hard, hard question of when do you start Ozempic on somebody who's overweight but doesn't have overt metabolic dysfunction, and the answer is probably not as your first line and you do the lipids and you do the blood pressure things, but it's interesting to see the discourse around these drugs, which is I don't think anybody has a problem with putting somebody on a high blood pressure medicine that they're gonna be on for decades and we did that before we had decades. Of data establishing their safety and long term, uh, long term efficacy and so why are GLP1 agonists so different and there's a very moralistic side of how people discuss these drugs and I am certainly like the decision about like what's morally right and like is the weight loss fair or unfair that's so far above my pay grade that I'm not even gonna touch it with a 10 ft pole. It's these are hard questions to answer and I'm not gonna pretend that I have a, a smart, a smart thing to say about them. I've, uh, in the old days, which I'm familiar with, um, high HDL was good. I've been reading now that high HDL carries increased risk. So can you talk about that? The HDL question is really, really, really interesting, and the history of drugs that raise HDL is just like billions of dollars in wasted, uh, wasted money because drugs that raise HDL don't seem to lower cardiovascular disease risk. There is a difference when you're seeing a patient of someone who has high HDL versus somebody who has super high HDL. The patients who have really like I, I'm talking HDL levels over 100 150 mg per deciliter. Those patients, there are some rare genetic disorders that uh that are related to cholesterol transport that can be associated with those really, really high HDL levels, but those patients come in with a family history of early cardiovascular disease. I look at HDL in concert with the rest of the lipid panel, and I kind of think of a lipid panel as telling me two distinct pieces of information. The first piece of information it tells me is what is their LDL, which is telling me about what is their lipoprotein mediated cardiovascular risk. The other thing a lipid panel tells me is what is their HDL to triglyceride ratio? And if the HDL to triglyceride ratio is higher than 1 to 2, that tells me this person has the beginnings of metabolic dysfunction and the beginnings of metabolic syndrome, even if they don't meet frank criteria for it. And so the super super high HDL is very alarming. Uh, but it is also incredibly rare and it almost never comes in somebody who doesn't have a family history of cardiovascular disease. The HDL to me is much, much, much more useful when you're using it in relationship to the triglyceride levels because of the insight it gives you into metabolic health. I Good number. So, the bad numbers are the low numbers. And so under 30 to me is somebody who has metabolic metabolic syndrome, even if they don't have diabetes. You know, if you look at the epidemiology, being at 60 is better than being at 40, but that's across the population and for an individual I would look at it more as an integrative function of what's the lifestyle been over the last, uh, handful of months and so you know, anywhere between 50 and 80 I think is probably fine. Maybe even 90, but I, I would never use it as a target for treatment and uh I, I, I find it hard to know what to do with it when it comes back at 100 and somebody with no family history of heart disease and no plaque in their in their arteries in general, I, I, I, I will ignore it more than I'll use it. We have a couple questions online. um, do you have an LDL goal and how do you, uh, obviously some of the studies show that lower is better, how do you, um, balance that with the potential risk of things like hemorrhage or, uh, even cognitive changes with very, very low, uh, LDLs? Yeah, so the cognitive, uh, the, the cognitive changes, um, question is really, really interesting and. Um, you know, there are some statins that are lipophilic and cross the blood brain barrier, and there are others that are not. Um, and in general lower LDL is probably better for long term cognitive dysfunction because vascular dementia is a real thing and I think that most of our patients are more at risk for vascular vascular issues compromising their neurologic status than they are for drug induced changes in their neurologic status but I certainly have a a group of patients who tell me when I started the statin I felt stupid and then I stopped the statin and I felt like I was smart again and. You know whether or not I think that there's a plausible mechanistic basis for that like that is their lived experience and so I changed them from that drug and the PCSK9 inhibitors don't have that uh that same theoretical concern, um, but if somebody tells me they feel like they're not themselves being on a drug, I, I, I, I take that at face value and I'm willing to to make a change. The question about how low do you go comes down to how young were you when you had your cardiovascular event? What is your family history? How are your other risk factors well controlled? What are your values about taking medications? How much are like how many other pills are you on? What is your total pill burden? And so if you have a young person who had a heart attack or a stroke at an early age, then I want their LDL to be as close to zero as possible. And um if you if you're talking about a 75 year old who just has a little bit of coronary calcium and has never had anything happen and their parents died at 95 of cancer like I'm probably fine with an LDL of around 100 and so uh you need to it needs to be. Context dependent and it needs to be in uh in concert with what are the patients goals, how do they feel about the other things that that we're doing and if you look at what what are what's the natural history of cardiovascular disease, it's that you've gotten a benefit from being on that drug for being on it for a lot of years and if you've been on the right drugs for decades and then we need to stop them like I, I, I think that the risk reduction that you had from that time on the medications was uh was was time well spent. There's another question on drug induced metabolic syndrome and weight gain. Um, someone has a patient who someone online has a patient who, um, because of their medications had metabolic syndrome and has not been as responsive to medications like uh Ozempic, etc. Um, any experience with this population with these drug induced metabolic syndrome and, and weight gain and what would you do in a case where they're not responding to these medications that typically would help them with have a conversation about bariatric surgery or whether or not they need the medications and, uh, it's everything is risks and benefits and um the, the drug induced metabolic dysfunction. Is really, really challenging, um, you know, the anti-psychotics and other kind of psychogenic drugs tend to be the the biggest culprits there. um, there's, uh, there, there's a lot of, uh, discussion about the impact that statins have on insulin resistance and on metabolic syndrome where statins pretty consistently raise the A1C by like around 0.2. Um, but ultimately it's every patient's a little bit different and it's tough to make a blanket statement, but for a patient who has bad metabolic syndrome, it has not been, uh, responsive to the, uh, to the medical tools. bariatric surgery is a very, uh, reasonable and probably underused option. And now you went through A lot of the different types of diets and some of their potential benefits obviously their caveats when it comes to the studies showing those benefits. What is the conversation that you have with your patients overall in terms of what they should do based on, um, diet and what they should potentially be eating and not eating? Some people respond very well to hard and fast rules. Some people are able to take guidelines and apply first principles reasoning. Some people need a prescription. Um, some people do well with 80/20. I, I, so my conversation with a patient is like who are you as a person? What is going to respond very well to you and like how strict do you need to be with your rules and are you somebody who like the second the pins gets pulled out of the grenade, you're gonna just like not be able to get back on track for months and months and months? Or are you somebody who can go out for pizza for your birthday and like then the next day go back to what you were doing before and knowing yourself and like not bullshitting yourself is really, really hard to do. um, and so I have a conversation with patients that adherence is the most important factor. And what you can what you can consistently adhere to is the thing that's going to be most effective for you and um when it comes to low carb, low fat, Mediterranean diet, like if you're not, if your total calories are under control. Every diet probably works and uh ultimately everyone's a little bit different and some people are gonna respond really well to a carbohydrate restriction. Some people are going to respond really well to like macro nutrient tracking and calorie counting. It is so variable from person to person and so when I'm asking somebody about about this stuff, I try to just make myself shut up and not ask a follow up question and just let them tell me kind of how things are going and then try to offer like specific pointers for them but it's really it's just like it's it's the it's the hardest thing that I do. So, um, this is not directly related to what you were talking about, but every time, um, a certain newspaper publishes articles about aspirin not being needed, we get a slew of strokes coming in to the emergency room so one question from I guess the stroke world to the cardiology world is. Uh, yes, that data is out there, but what is your discussion in patients in terms of taking aspirin on a regular basis for primary prevention? Yeah, so aspirin for primary prevention is, uh, when patients ask me about that, I tell them if you go to 5 cardiologists you're gonna get 5 opinions about it. Aspirin reduces heart attacks and strokes period. It just comes with an increased risk of bleeding complications and on some level it's like which risk do you feel more comfortable with taking and. I tell, I that's literally the I would tell them like the magnitude of heart attack and stroke reduction is probably equal to the magnitude of bleeding risk and ultimately it's this, it's like the same, uh, it's the same theme which is What's your family history? What are, what are your other risk factors? Do you have known diverticulosis? Have you had peptic ulcers? Like, uh, uh, it's what, where do you fit into that spectrum of, of bleeding versus clotting and thrombotic risk and like vas vascular and thrombotic risk versus bleeding risk and everyone's different and some people will say, oh I could lower my risk of heart attack and stroke. Great, I'll take the aspirin. Some people look at that and they say, oh, it's a wash when you think about like net net. I don't. Wanna take it because I don't like taking pills everyone's different and I don't look at my, I don't think my job is to impose my values on uh on a patient. I try to give them a framework of like the lenses through which you can think about something and then I asked them like which type of patient are you? and you're the person who wants to take an extra pill if it's gonna lower your risk of something bad happening, or you're the person who if the magnitude of it is small, you'd rather be left alone like you're in you are an adult and I'm not your mom and so that's that's what my conversations are like. Published December 14, 2023 Created by Related Presenters Gregory Katz, MD View full profile
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