Steven Nissen: Reflections of a Master Clinical Trialist

In episode 14 of the CardiOhio Podcast, we interview a legendary clinician, teacher and trialist  in American Cardiology, Dr. Steven Nissen from the Cleveland Clinic. 
We review his contributions to contemporary trials and lipids and diabetes, as well as his analytic approach to reviewing clinical studies. We then discuss his most recent contribution to the field of lipid therapy, the CLEAR outcomes study published earlier this year.

For additional information on the discussed studies:
Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes
Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients (CLEAR outcomes study)
Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients

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Transcript

0:05

Welcome to the Cardio Ohio Podcast, a production of the Ohio Chapter of the American College of Cardiology. This is Can Greyal in Columbus, Ohio. This is Ben Allen Cherry Cardiovascular Imaging fellow from Cleveland, Ohio. More information on the podcast, including past episodes, is available@ohioacc.org. And now for today's,

Ben: 0:31

All right. Welcome back to the Cardio Ohio podcast. I'm here along with my co-host Kenny Graywall. We have a very special guest today, Dr. Steve Nissen, who is chief Academic Officer at the CDE and Arnold Miller Family Heart and Vascular Thoracic Institute at Cleveland Clinic. But I would be remiss to try to start to name all of the hats he has worn in the past. More importantly, one thing he did with me is he was part of the recruitment when I went to Cleveland Clinic as a fellow. And I have rounded with Dr. Nissen in the I C U several times and, and learned a lot from Dr. Nissen. So I wanna introduce Dr.

Steven: 1:10

Nissen. Well, thank you very much for that nice introduction.

Ben: 1:15

so, Dr. Nisson, we wanted to start with first, just to let the audience kind of hear a little more about your story. We, we asked for like a little short biography of our of our guests and, and kind of just if you just take us through an, a whirlwind tour of, of sort of the places you've been since medical school the hats you've worn, especially at the Cleveland Clinic and what you're currently doing now.

Steven: 1:37

Okay, so very quickly I went to University of Michigan Medical School and I then went to the University of California Davis for internal Medicine residency. And it turns out there I met an interesting character, a guy by the name of Anthony Daria. Tony Daria, who many of you know, went on to become editor of the Journal of the American College of Cardiology. But You know, he recognized that I had an interest in academic cardiology and so he offered to take me with him when he took the job as chief of cardiology at University of Kentucky, and I went to University of Kentucky and I did my fellowship there very quickly. I was a two year, it was nominally a two year fellowship, but frankly it was more like a one year fellowship. And then I was made the director of the coronary intensive care unit, which I. Loved and did that for a number of years. Did some wild and crazy things in Kentucky. Started a helicopter service and used to fly out almost every night and pick up acute mi, give'em thrombolytics in the, in the field, in rural Kentucky, and fly'em back to Lexington for their, their cath, which was acquired at 90 minutes In those days, per protocol. I then got recruited to the Cleveland Clinic by the then chairman Eric Topel as vice chair, and came to the clinic in the early 1990s, 92, 93. And while I had been at Kentucky, I had developed intravascular ultrasound, had done some of the initial work with it and brought the technology to Cleveland and began to refine it. Developed a core imaging laboratory to make measurements. And while everybody else in the field thought that intravascular ultrasound ivus would be used to guide interventions, I thought it was ideally suited to measure atherosclerosis. And so I convinced a company that had this new drug called Lipitor and that we could show whether or not. Attaining a lower cholesterol level could reduce the progression of coronary disease. And so in about 1997, we designed the reversal trial. We finished it and published it in 2003. It was got a huge amount of attention because it showed that lower levels of L D L were associated with less. Disease progression. It actually ended up on the front page of the New York Times, and I then went on with a team that I had developed here at the Cleveland Clinic to do an 11 more intravascular ultrasound trials over the next decade or so. And that for me was an entry into the larger world of large randomized clinical outcome trials. And so it was just one step at a time. Pull yourself up by your bootstraps, do the work, you know, publish it and stand behind it. And hopefully if you do that, good things will come your way.

Ben: 5:05

That's a that's an awesome recap, Dr. Nissen. And I think we're gonna have a separate podcast for the helicopter stories

Steven: 5:10

for sure. Oh my God. I can tell you war stories that you wouldn't even believe.

Kanny: 5:17

So Steve I know you've been also a, as you progressed from the IVUS trials into some of the other randomized trials and lipids and other topics, you kinda led. This this kind of change in how we approach trials in terms of safety events with your experience with Glitazone. Yeah. And we were just curious like how you got interested in that specific aspect of clinical trials and which has now kind of become a standard in terms of looking at, safety

Steven: 5:42

outcomes. Well, it's actually interesting because, you know, you have to be prepared. For this sort of finding. You know, I don't, I didn't go looking for any of this, but in the year 2001, I got asked by the F D A to serve on the Cardiorenal advisory panel, and the first panel I attended was a review of a gastrointestinal claims for a drug known as Vioxx. And I looked at the data, you get thousands of patients of data from the F D A, and I saw that in every study. There seemed to be more cardiovascular events in the people that got RO coxib compared with other drugs. And so we collected all of the data that we could and. We published a manuscript in JAMA that raised questions about the safety of, of Roha. Coxib, otherwise known as Vioxx. Took a terrible beating. It was really awful. Actually the study was led by Deb Mukerjee, who was a interventional fellow at the time and now chief of cardiology at an institution in, in Texas. And, You know, we got beat up by the pharmaceutical industry, but we stu stuck to our guns, and four years later, the drug was withdrawn for unequivocal harm. Then in 2007, I had concerns. About the diabetes drug glitazone known by the brand name of Avania. I had noticed that in clinical trials, again, published trials were relatively limited, that the cardiovascular events seemed to be trending in the wrong direction and the drug was being marketed for cardiovascular benefits, and it didn't make any sense to me. So I went looking for more data. And there was almost nothing, and then I hit a gold mine. It turns out that the former attorney General of New York State Elliot Spitzer, who later fell from Grace, but Elliot Spitzer sued the maker of Rosa Glitazone GlaxoSmithKline because the company had hidden data on hazards. From their, one of their antidepressant drugs in teens and children, teens, young adults, where there was increased suicide and suicidality. The settlement was for$1, but with the requirement that the company post all of the results of their clinical trials on a website. The website was fairly well hidden, but I found it. And I downloaded all of the data on Rosa Glitazone. There were 42 clinical trials, 35 of which were unpublished, and my lead statistician, Kathy Wolski, and I huddled in my office for a couple of days, wrote a New England Journal of Medicine manuscript. Which was a meta-analysis of all the available data that we had access to because of that previous lawsuit. Please keep in mind that up until this point in time, a company could do a clinical trial. They didn't like the results. Nobody ever got to see it called negative publication bias, and, and a lot of academics went along with that. Well, what we saw was a 30 to 40% increase in. Myocardial infarction and a similar increase in cardiovascular death with glitazone compared with other drugs. When that thing hit the, hit the streets, you know, the New England Journal of Medicine reviewed it and published it in 21 days, and when it came out, headline news, you know, it was just incredibly intense. But the result, Was that at an f d A advisory board meeting in 2008, I proposed that they no longer approved diabetes drugs simply because they lower a biomarker blood sugar, that they had to do cardiovascular outcome trials as a condition of obtaining approval. And we worked out a, a system, you know, I proposed it. The panel agreed the f d A panel agreed and it became a. The rule and in the years since then, all of the trials, you know, with the SGLT two inhibitors, the GLP one agonists, all of the data that came out was a result of Seeing a signal with Rosa Glitazone acting on the information, being decisive about writing up the manuscript and publishing it and standing behind the findings. And you know, so there were two pretty large, very large, I mean, headline news, drug safety issues. You know, I got accused by some people who, for various reasons, wanted to believe it, that I was somehow. An anti-drug industry, which of course is not the case. We need a great drug industry to develop new therapies for patients, but we have to be prepared to tell people what works, what doesn't work, and what's harmful, and to provide equal weight. To the findings, regardless of which direction they

Ben: 11:34

go. And, and Dr. Nissen, I'll just jump in there because I remember hearing the story as a first year fellow when we were rounding in the unit, and I, I couldn't believe it. And I wanted to highlight for our listeners that. You know, indirectly you probably had a lot of pharmaceutical mafia people come after you, but at the same time, the this, this sort of action is kind of why we have SGLT two s and GLP one s because of that push for having cardiovascular outcomes. So, I mean, you're saying the story, but I think it's even bigger than, than this because this has shaped some of our newest drugs that we use in all of these patients.

Steven: 12:11

No one would be able to use these drugs if we hadn't required the trials because you know, the pharmacy benefit managers would say, well, why should we pay for a drug when all it does is lower blood sugar, the same way of sulfonylurea or any other drug lowers blood sugar. So it turned out it actually helped the industry, but it helped patients. That's what really counts. And you know, I proudly stood behind the data. It was a very difficult time because you know, I can tell you that if you do take on a multi-billion dollar industry, they're gonna come after you and you better have thick skin. And you better be willing to stand your ground. But I'm pleased with how it all worked out. And I do think you're right. There have a number of people have written about what happened, and in fact, there was 172 page report from the US Senate after they had held a bunch of hearings that goes into all of the gory details, one of which was unbelievable that when we submitted the manuscript within 24 hours, one of the reviewers. Who had a financial relationship with GlaxoSmith Klein gave him a copy of the manuscript while it was in review, which is wow considered highly unethical. And as a result the company knew it was coming. And they plotted their strategy on how to character assassinate The two authors myself and, and Ms. Wolski, and, you know, this all came out in the Senate report that the, the, the senators discovered with subpoenas the actual facts that had gone from the, from the reviewer to the company. That had given them a copy within hours of its submission of the manuscript I'd submitted to the New England Journal.

Kanny: 14:10

That is a, that's a tremendous story. We, we are familiar with it, but yeah. But it's great to hear, it's great to hear her firsthand accounting of it though. That's tremendous. So, so Steve, before we spend the last 10 or 15 minutes talking about some of the newer. Trials. Yeah. I did want to ask you, you've spent, you have so much experience conducting trials that have been so seminal, and of course you review trials as well for some of our young, early practi, early career practitioners, our fellows in training our nurse practitioners. as you know, the, the medical literature has just exploded and specifically the cardiovascular literature. So when you, when you approach a trial as a reader, as a clinician in your clinician hat, And you're trying to determine, the relevance and how it may apply to your patients. Are there a few things you focus on to help kind of, clear the wheat from the shaft and figure out which, which studies really are gonna have impact and, and, and contain actionable information? How do you approach, you know, well, that's

Steven: 15:10

a great question. You, you certainly have to dive deep and I find that some of the best information. Is actually in the supplement that almost nobody else reads, and I'll give you an example of that. You know, the Reduce It manuscript came out with a Casa Pyl, otherwise known as vascepa, and it just seemed too good to be true. And so I'm looking at the supplement and and buried on the last page of the supplement or nearly the last page, I find a single line that shows what happened to high sensitivity C reactive protein in the two treatment arms. And it turns out that in the control arm, which was a mineral oil placebo, there was a 30 plus percent increase. C-reactive protein unheard of. And what that led to was a series of investigations, and I think there are a lot of people who now agree with me that basically it's a false positive study that instead of using a neutral placebo, the trial used a placebo that was toxic. And so the apparent benefits of ACO ethyl were actually due to the toxicity of the control of the placebo and not to the benefits. If I hadn't looked deeply into that supplement, And everybody else missed it. Nobody. Nobody really saw it. And then later on, Paul Ricker did an analysis of blood samples from the trial. And every inflammatory marker you can imagine went. Incredibly bonkers up with the mineral oil treatment group. And so it's a classic example of a drug that got a, got a label from the F D A. It's widely used. It is not, it does not produce favorable effects. It's a false positive study. Yeah,

Ben: 17:19

and I think Dr. Nissen, that that point of diving into the. Like the details, the supplemental indices, it's, I guess the challenge is there's so many of these clinical trials that come out and in general, cardiology, you are spanning prevention, imaging, when to intervene on patients. How do you, is there a guide you use, like do you follow certain journals specifically? How, what would be your words of advice for, for the general practitioner to make sure they're staying up

Steven: 17:46

to date? Well, I think first of all, the tier one journals, which are, you know, jama, new England Journal and the Lancet a lot of the most weighty research appear, not all of it, but a lot of very most important research appears in those three journals. And I try to look at them and I think there is time for most cardiovascular practitioners to, to read. The cardiovascular studies that are published in those top three journals, I mean, that's just not a big lift. And, you know, look, I work very hard, you know, I'm one of the oldest people in our department, but I'm the first one there in the morning. I get there at four 30 or five in the morning every day, off and on weekends. I spend the time that I have as productively as I can, and I do read the literature carefully so I can stay informed, and it helps you pose the questions. That you wanna ask? You know it's kind of interesting because there are always people that are gonna push back. I was just remembering again about the whole glitazone controversy. And when I propose requiring outcome trials for diabetes drugs, many people in the diabetes community looked me in the eye and they said, if you do this nien, we will never have another diabetes drug. Because no company's gonna make the investment in doing the outcome trials. Well, you can see what's happened since then up just a proliferation of very, very good trials.

Ben: 19:23

Yeah, I definitely agree that that was a courageous move. And, and kind of before we jump into now, the, the current lipid trials, including clear Yeah, I, I did have a question. Sometimes we have patients listen and. I think it's, it's sometimes a an art to explain to them the importance of enrolling in clinical trials with the chance that they get a placebo. Obviously patients want to be treated. How, how have you kind of navigated that as somebody who's run several clinical trials? Yeah, yeah. Even for example, in the mava campton trials Yeah. That you've been involved in. How do you, how do you kind of approach patients in that way?

Steven: 20:02

Well, first of all, patients who volunteer for clinical trials, it is a noble endeavor and they do so for very good reasons. They do so they will say to us, we know this may not help me, but if it helps somebody else, I think it's worth it. The other thing that is really amazing, there have been multiple studies published that people that are in the placebo harm. Of randomized trials do much, much better than the general population. Why is that? It's because they get very good medical care. They get managed to, you know, with state-of-the-art control of their risk factors. They're seeing people frequently, you know, the nurse coordinator and or the, the principal investigator at the local site. And so they do better. And so being, just being in a clinical trial gives you an advantage over people who are not in a clinical trial. And that's the truth. There's lots of studies that show that.

Ben: 21:04

Yeah. And I can imagine once, once patients wrap their head around that, but also if they have the courage to continue to, to be somewhat altruistic, it really shapes the field because as much as the, the clinical trial is running the trial, it's the patients who are involved who push it forward as well. You bet. So, Dr. Ni, can you just tell us because you noted this, Difference in the omega-3 trials. Can you just tell us how from the Cleveland Clinic group, there was a, a, not a rival trial, but a, it was sort of proof of concept trial that was conducted as well? Yeah. How did you kind of

Steven: 21:41

start that? Well that was started actually our trial was with a different product. Very similar in many ways, to a Casa Pyl or vascepa. It was just a little different formulation and we ran the trial. It was, it was actually larger than reduce it and it showed no benefit. There was just nothing and. We said to ourselves, I, you know, this was, this was finished just a few months after reduce it. We said, how can one fish oil that does low risk triglycerides a little bit, does a few other things, show a 25% reduction in morbidity, mortality, and another product that is almost the same chemically show zero benefit. Something had to be wrong there. And the, the, of course, the, I, I had a very good idea what it was. And it was the, the problem with the placebo we used and we knew, by the way, that mineral oil was probably toxic when we designed the strength trial. We did was, again, similar in size, you know, 12,000 patients, I mean bigger in size, 12,000 patients. We chose corn oil as the placebo because we thought corn oil was about as neutral as you can get. We thought olive oil was beneficial. We knew that there were issues around mineral oil, so we chose something deliberately. That was neutral and there was no difference between corn oil and the same four gram dose that was used and reduce it with just a little bit different product. And so at the end of the day, it just didn't seem possible that these two trials could have completely opposite results. Something else had to explain the differences.

Kanny: 23:44

Yeah. Thanks Steve. That that makes sense to set the stage for our last 15 or 20 minute discussion about, you know, clear and. Other agents. I'm, I'm really fascinated by, you know, the concept of statin intolerance. I was reviewing some of your previous articles about that in the last several years, and I, I think you have a very interesting definition of it. And one thing you raised in one of your, your editorials a few years back was a concept that perhaps with statin trials, you know, the fact that patients have to be recruited into these studies, that somehow we're selecting a group of patients who are less prone. To the side effects because, you know, just like you, I'm a clinic clinician who's in clinic almost every day taking care of patients. And you know, the concept of statin intolerance comes up almost daily, multiple times with our patients. And of course, when you look at the literature of, of the incidents, there's such a dichotomy between what we see in the real world. And it looked like in some of your editorials, you addressed that. So I was wondering if you could just review how, how you put that in perspective with some of your

Steven: 24:50

patients. Well, first of all, it is a very controversial topic. You know, there is a group in Europe, in, in the UK that thinks it doesn't exist. There are other people that Build their entire careers on the treatment of patients with, with statin intolerance. You know, my, I have a very pragmatic view of this. There's two things I really think people should know. One is that most of the clinical trials that have been conducted have a run-in period where you get the drug. And, you know, if you have an inability to tolerate the drug, then you're not randomized. So you have this, this run-in, in advance of actually conducting the trial. And so you remove from the study all the people that are statin intolerant and the other Quest Other issue is really a very practical one. If a patient comes in your clinic Kenny and says, You know, I have tried the statins, I've tried multiple statins. I can't tolerate the statins and I won't take a statin. And they have a very high L D L in their, you know, they've had a previous event. What are you gonna do? You, you can't force a patient, take a drug they don't wanna take. And so we have to have practical alternatives, even if you think that it's in their head from that. For them it's real.

Kanny: 26:22

Absolutely. Well, thanks to you and other trialists. Fortunately we we're increasing our armamentarium now. Yeah. So that so that we do have many more options.

Ben: 26:34

we're gonna focus on the newest on his newest trial, the clear trial. I'm gonna just give a brief summary so that Dr. Nissen doesn't have to start from, from ground zero here. The clear trial published in New England Journal was randomized about 13,000 patients. Who are at high risk for atherosclerotic cardiovascular disease and who are unable to take more than a low dose statin to either the placebo arm or beo acid. And that's the drug that is being tested. And so they randomized 13,000 patients. And their primary outcome was a, a composite, the standard, major adverse cardiovascular event, composite of death from CV causes non-fatal mi, non-fatal stroke and need for coronary revascularization, and they found a a, a significant reduction. In Mace. And, and kind of the, the main things that we thought that this was so applicable clinically was because it, it adds to the armamentarium for our primary prevention patients who are at high risk and don't have options because of intolerance. And so from there, just with that background, Dr. Nissen I kind of just wanted to ask you from the, from the get-go, what did you foresee when you were initially starting the design of the trial? Well,

Steven: 27:47

we knew that beo acid is a pro-drug. It's not active in peripheral tissues. It gets taken up by the liver where it gets converted to its active form. And so if it's not active in peripheral tissues, it can't cause the kno myalgias that many patients complain about when they take statins. And we had pretty good evidence from smaller trials that it didn't seem to produce the kind of musculoskeletal problems and statins. Produce. So it made sense then to study this drug in statin intolerant patients. Now, just wanna make sure you understand that about 80% of the patients were on no statin. They couldn't tolerate any. And about you know, 20% or so, were on less than the lowest approved dose of a statin, like on 10 milligrams of atorvastatin twice a week. That sort of thing. So these are really people that are statin intolerant and we made'em sign a statement that they would not take a statin even though they knew statins could reduce their risk of heart attack, stroke, or death. So we did this in an ethical way. I thought it was very important to do that. And we were able to find at 1,250 sites in. You know, something like 32 countries the patients were enrolled and, you know, we've went on for a number of years. We followed them for about 41 months. And of course, there's nothing in the world quite like unblinding, a trial you've worked on for many years and finding out whether it worked or it didn't work.

Kanny: 29:33

And I, I know that the trial did include almost 50% women, which is nice to see as well. Yeah. So I was curious though, you do have kind of a mix of primary and secondary prevention patients in the study. Have you analyzed any differential effect in, in those two groups, those with known c a d and those with, with risk factors

Steven: 29:54

only? I thought you'd never ask. So you have to come to the a d A meeting. It's on the program where we are going to present detailed results in the 30% of patients, 4,200 patients. They were primary prevention. They had high risk factors, but they'd never had an event. And if you looked really carefully at the supplement, you will notice that there appeared to be a more favorable effect in the patients that were in the primary prevention strata than those that were in the secondary prevention. We're gonna tell you a lot more about that. I'm gonna present it at ada. And it will be simultaneously published in a major journal.

Ben: 30:43

And I think that's, that's good. That's the hook right there, Dr. Nissen. And also another plug for you for us to take a look at the, the depths of these articles, including the supplementary indices. Yeah. When you, when you talk about bedo acid, a lot of, a lot of what people say about statins is this pluripotent effect including on anti-inflammation. And c r p has been used as a, as a marker for this. Can you just help us as, as far as statins, we kind of understand some of that. But as far as beo acid, what's its relationship to inflammation that you found in the trial?

Steven: 31:15

Well, keep in mind that beo acid works in the same pathway as statins, but upstream, and it has quite intense anti-inflammatory effects. We got about the same amount of reduction in high sensitivity C R P. As we got reduction in L D L cholesterol, so it has two potential ways to benefit patients, both as an anti-inflammatory. And we now know that anti-inflammatory drugs like Colchicine or Kinumab do have cardiovascular benefits. And of course, we've known for a long time that L D R reduction has benefits. Baic acid does both. What we didn't study. And I wish we could have, but we couldn't for a lot of regulatory reasons, is the drug is available, Beto acid, both as monotherapy and in combination with ezetimibe. The combination with Ezetimibe produces a 35 to 40% L D L reduction. It's about the same as 40 milligrams of simvastatin, and so we can get a pretty robust L D L reduction with that combination without having to give a statin to those patients that simply won't or can't take a statin.

Ben: 32:34

Yeah. So I think that that's awesome that that offers another option. Yeah. Now to, to speak to this point though what has been brought up is something, something about cholelithiasis, something about gout. Yeah. As far as the, the true side effects, because we know what statins cause. How would you frame that from what you've seen in the, in the patient outcomes and, and maybe just how you would translate that clinically. Do we use it in patients with gout already or use it with caution, et cetera? Yeah,

Steven: 33:00

I would be very careful and probably I would not use it unless I really felt I had no other option in patients with a strong history of gout. Unless, of course they had been on a uric acid lowering agent for some time and had very good, you know, low uric acid levels. Those people I would be okay with. But, you know, I would worry about triggering gout. Now look, if you, if you wanna trade off gout, Versus a heart attack, I'd kind of take a gout attack any day of the week. Having said that, you know, we don't want to be cavalier about these things. We had not previously seen csis, but there was an excess, about 1% excess of colonese. In the Baic acid group, you know, again, it was generally not something that led to surgery or sepsis or anything like that, but it was an excess, and people need to be aware of that. Look, let's be very clear, there is no such thing as a free lunch. Every drug we give patients has pros and cons. It's important, I think, for clinicians to know the upside. To know the downside and to make an educated decision with the patient at the table, so-called shared decision making. Lay out the risks, lay out the benefits, make a decision together on what direction to go.

Kanny: 34:29

Steve I was also there in the audience at a ACC C when you presented this to much excitement. I, I know there were, there was one question asked at that time about the fact that, you know, you had a. Combined out outcome, not a mortality benefit directly. Yeah. And yeah, and you know, I'm wondering do you think that's relevant or do you think the fact that most likely this is gonna be used in combination with Ezetimibe and further LDL lowering, and of course Ezetimibe has pretty good evidence base behind it now, do you think that makes the mortality issue a little less relevant?

Steven: 35:01

Yeah. Okay. It's not irrelevant. It's highly relevant, but here's the issue. Both large PCSK nine inhibitor trials, one of which was 27,000 patients had absolutely no benefit on mortality with a 50% L D R reduction. Almost all the modern trials in secondary prevention patients have not shown a reduction in mortality. We didn't see it for Alloc, for Evolocumab. You know, I could go on and on and on about the trials that did not show a death benefit. Why is that? It's because of everyone listening to this podcast. We've become very good at treating people with acute mis. People don't die of acute MI very often anymore. They may die. 7, 8, 10 years down the road. Or they may ultimately later on develop heart failure, but they don't die in the short run. And so I don't think we're gonna see lipid lowering therapy even with these very powerful L D L lowering drugs. Reduce mortality. We didn't see with baic acid, we didn't see it with PCSK nine inhibitors. It's just too much of a reach in the contemporary era.

Kanny: 36:24

Yeah, and I think that does make complete sense, so thanks for clarifying. So as we kind of put this study with Bedo acid in perspective with so many other, you know, existing or agents that are on the way, I'm just curious to finish up in the last five minutes or so how you approach, you know, all of the statin alternatives now in your mind. Obviously we know that for primary, excuse me, for secondary prevention patients, we're always gonna start with a high dose statin. And we know, we know we have very good data about target LDLs. But how would you rank this drug with say, PCSK nine inhibitors, which you just mentioned, as well as Zein and some of the others as you approach a patient who say statin intolerant. And then as a follow up, a patient who doesn't get to go. On the maximum statin dose they can tolerate.

Steven: 37:18

Well, Kenny, you said something interesting, which of course, which I agree with, which is that we have good idea of what target staff for L D L. Unfortunately, we haven't been able to convince our guideline writers that that's the, that that's the case. But having said all of that I do believe that lower is better. And the higher the risk the patient, the lower you wanna go. Statins are the first line drug. They're the second line drug, and they're the third line drug. And we try, try and try again. If we get'em on, get patients on a statin and their l d L is still above where we want it. The natural thing to do is to add ezetimibe because it's generic, it's inexpensive, it's very well tolerated, very safe. There will be people that will not get there. With adding ezetimibe, and they will need a PCSK nine inhibitor. And that includes now lyran, which is a, you know, very attractive drug because it's so long acting that you only have to give it twice a year if people cannot tolerate evidence-based. Doses of statins, well then we have alternatives like beo acid or beo acid with ezetimibe, and if they need a lot of L D L reduction, then even beo acid with ezetimibe may not be enough, and we may need to go to a PCSK nine inhibitor. Here's what's really fantastic. We have a lot of tools in the tool chest, and we can pick them based upon the pharmacoeconomics patient need. What patients tolerate, what our goals are, but I hope everybody will, will remember and please share with me this view that the higher the risk, the lower, we wanna take. The L D L. The evidence is compelling that lower LDLs lead to reduced rates of event and re reduced rates of disease progression.

Ben: 39:22

Dr. Nien, that's you said a couple key things there that we'll highlight and, and I think first, second, third line is statins. And, and like you just said, even just this past week, I've gotten asked by some of my interns colleagues is, is there ever a too low in, in some high risk primary prevention and secondary prevention? And I think you. You clearly state that and we'll have links to some of these landmark trials, including your initial New England Journal piece about Rozi, Rosie Glitazone. Yeah. To to end this is more on like a philosophical topic. Yeah. Dr. Nisson, I've had the pleasure of working with you for now, three and a half, four years, rounding in the unit with you for several hours each day, and, and I've, I've kind of noticed and, and heard some of your stories, but. You know, after, after kind of seeing through different eras in cardiovascular medicine, being a, a major player in that, you know, we have a lot of people who are listening who are early career and some who are really motivated mid-career and late career docs. What motivation would you give them? What, what words of advice would you give them on how to stay on top of things? How to keep interested. And, and how to push your career forward. How, what would you give like a, a last parting statement? Well,

Steven: 40:33

I could tell you is there's no, there's no easy route, you know, and get to work early, you know, keep your, your eye on the literature you know, dream big. Never believe that you can't accomplish something. I'm gonna tell you one final story. There was a, a guy who at the time was a fellow who got the idea that may, he saw me giving nitropress eye to patients with aortic stenosis, and he said, shouldn't we study that in an R C T? So he designed a 25 patient, R C t. That we did in the C C U showed that Nitro Proxide made people with critical as better, and he got it published as a fellow in the New England Journal of Medicine. Dream Big.

Kanny: 41:25

That's fitting Steve. Yeah, that was my only question is does Ben really show up for rounds in the C C U at four 30 when you get there? Cuz I have a hard time

Steven: 41:33

believing that. Well, what happens of course, is the fellows know what time I get up, so they always make sure they get there a little before I

Ben: 41:40

do. I'll tell you those weeks. Breakfast is just earlier. That's it? Yeah.

Steven: 41:46

I start rounds at seven only because the residents would be furious. It would be if I made'em round at six, I just assume round at 6:00 AM

Ben: 41:55

That's so funny. Hey, Dr. Nissen thanks so much.

41:58

Thank you for joining today's podcast. For more information about the speakers or the topics, please go to Ohio acc.org,