Announcer:
0:00
Welcome to MedEvidence! where we help you navigate the truth behind medical research with unbiased, evidence-proven facts hosted by cardiologist and top medical researcher, Dr Michael Koren.
Dr. Michael Koren:
0:11
Hello, I'm Dr. Michael Koren, the executive editor of MedEvidence!, and I have a really special guest today Dr. Paul Ridker. Dr Ridker is the Eugene Braunwald Professor of Medicine at Harvard Medical School and attending at the Brigham and Women's Hospital. And this is really exciting for me, Paul, because we've known each other since medical school, so it's fun to watch your career your meteoric career, by the way and I've learned a lot from you over the years and I appreciate that. I'm going to highlight some of those things and I want you also to share some of that with our audience, in particular, the fact that Dr. Ridker is considered the world expert in inflammation and cardiovascular disease, and Paul has dedicated his entire career to this. So, Paul, thanks for being part of MedEvidence! And why don't you start us off by telling us how you got interested in inflammation? How do you go from medical school to becoming this inflammation guru?
Dr. Paul Ridker:
1:13
Well, first, Mike, it's great to see you. It's a real pleasure to be on your podcast and I'm not surprised at all. You're a terrific communicator and I think the way that you think about medicine is a little out of the box, which is exactly what it should be, and it's really a pleasure for me to be here today and to reconnect with old friends it's always fun. The whole story about how this inflammation biology piece began is actually an interesting one that you'll really appreciate.
Dr. Paul Ridker:
1:38
When you and I were in our training years and in my case you know, across the street at the Brigham, rotating through the coronary care unit it occurred to me that something was wrong with the textbook. The textbook said everybody who came in with an acute myocardial infarction should have certain characteristics high blood pressure, smoking, cholesterol, etc. And it was pretty apparent that that just wasn't true. There were a lot of people showing up who had major vascular events. 25 to 30% had no major risk factor at all, and that began us struggling with, well, what's really driving this? That we're sort of missing? That shouldn't surprise people, by the way.
Dr. Paul Ridker:
2:18
Textbooks change over time and our knowledge base changes enormously over time. We didn't start with inflammation. We actually started looking at what we call thrombosis, how your blood actually clots. It was an interesting thing published in papers, but it really wasn't telling us about how to take care of my patient sitting in front of me, which is really the ultimate goal. The inflammation piece starts because inflammation, which is really how our body fights infection, how our body deals with foreign objects, things that aren't supposed to be there, and how you mount a response to that, is really important for ultimate survival. So I'm going to try to avoid getting jargon on you here, but let me take back about 30,000 years. Imagine you're living in a cave somewhere and you just want to survive.
Dr. Michael Koren:
3:14
I still live in a man cave, by the way.
Dr. Paul Ridker:
3:17
Yes, I can tell, and I know you're still playing guitar, I think, as far as I know. So that's great.
Dr. Michael Koren:
3:25
Well, keyboard but-
Dr. Paul Ridker:
3:25
I remember music from way back when.
Dr. Paul Ridker:
3:26
Yeah, but 30,000 years ago, childhood infection would kill the vast majority of people who were born. Measles, malaria, mumps, schistosomiasis, you name it you need a pretty good innate immune system to survive that. You need a pretty good innate immune system to survive that. The second thing that killed a lot of our forebearers was the saber-toothed tiger, if you like. You had to have a coagulation system that would survive bleeding Very important for women who used to die so commonly in childbirth because of hemorrhage. And the third piece that people may not think about is, in a pre-agriculture universe starvation. So starvation would kill a lot of people. And what do those three things have in common? Well, it's a insulin resistant that's how you get by the starvation. Pro-coagulant that's how you get past the saber-toothed tiger. And pro-inflammatory that's how you get past these infections. So our immune system is designed to help us survive these challenges of life when humans began. But you know, I live in Boston. We don't have a lot of saber-toothed tigers. Women now survive childbirth because we have fantastic medical care and childhood infections are largely dealt with with immunizations and vaccines.
Dr. Paul Ridker:
4:49
But that survival benefit of having this activated immune system in midlife becomes a hindrance and I think our patients kind of know this, because all the things that happen later in life not just heart attack and stroke and cancer, which we're going to focus on, but arthritis, the breakdown of our bodies in general I played tennis last night so I'm a little achy this morning these are all consequences of living longer.
Dr. Paul Ridker:
5:22
Now I'd like to continue to live longer. I think as long as we have a good mind and a healthy body, it'd be lovely to live in our 80s and 90s and maybe even longer. But from a strictly evolutionary biology perspective, all we're really supposed to do is live long enough to reproduce, have kids, get our children launched and then, as I laughingly sometimes say, everything else is extra genetic debris, but it's debris we all want in midlife and later. So the question is, how do we dampen down this inflammation that was so useful to survive early life? That's coming back to haunt us in later life. And the reality, Mike, is that almost all the diseases of chronic aging and in particular, as cardiologists, we focus on heart attack and stroke, but it's equally true of cancer and other things. They all turn out to be driven, at least in part, by this chronic inflammatory response.
Dr. Michael Koren:
6:19
And that's very, very well said. So I'm going to jump ahead 30,000 years and talk about what was starting when we first became cardiologists, which is statin drugs, and both of us have been very involved. You were the lead investigator in a very important study called JUPITER Study, using a drug called rosuvastatin, so why don't you start us there in terms of the more modern journey with regard to treating inflammation, particularly the use of cholesterol drugs and where their limits may be found?
Dr. Paul Ridker:
6:50
Sure. So, certainly as cardiologists, I think we'd all agree that the single most amazing invention made by a guy named Akira Endo, by the way, who was a biologist in Japan who just passed this past year. So I went to a memorial service with him recently at one of the atherosclerosis meetings he discovered the very first statin and, interestingly enough, he came out of industry. He was interested in fungi, he was a chemist, he knew how to isolate enzymes and he figured out this enzyme that would change the way our bodies metabolize cholesterol, and that discovery would lead to all the drugs that today we know as statins and, as you point out, most people take atorvastatin or or resuvastatin, sort of the modern ones. So our guidelines told us for years, correctly, that we should lower the so-called bad or LDL cholesterol, and we have lots of clinical trials consistently showing in this that as you take LDL bad cholesterol levels down with these statin drugs, patients do better. They have fewer heart attacks, they have fewer strokes. There's no controversy about any of that. That's just rock solid data. What was puzzling to us, however, was the speed with which these drugs work. You start to get benefits of being on a statin well before the cholesterol-mediated effects actually occur and we noticed that there were patients who were benefiting from these drugs who actually had pretty low cholesterol levels to begin with. So, Mike, you're remembering very well around 2000, so almost 25 years ago now we designed this clinical trial called JUPITER, which said well, we had recently shown that these statin drugs not only do they lower cholesterol, they also lower a biomarker of inflammation. This is a mouthful. It's called high-sensitivity C-reactive protein, or hsCRP. That's going to be important because that's the thing that we actually measure in clinic to say, aha, my patient has a little bit of inflammation, a moderate amount of inflammation, a lot of inflammation. So that hsCRP test we're going to come back to it, I'm sure is going to be quite important. But the point is we had shown that statin drugs actually lower this inflammatory marker, the hsCRP, and we had tantalizing evidence that maybe people with a high CRP would benefit from being on a statin even if their cholesterol levels were low and they didn't even qualify for a statin.
Dr. Paul Ridker:
9:15
Anyway, fast forward. We published these data in 2008. It's a nearly 18,000 patient multinational, global trial, critically of people who were primary prevention. So no prior heart attack or stroke, healthy men and women, middle-aged folks who would never qualify to be on a statin because their cholesterol levels were actually pretty low. But they all were selected because they had this marker of inflammation. They all had an elevated hsCRP, a level greater than two to qualify for the trial. And what's so remarkable is that in this study, where nobody would have gotten a statin because, again, the whole idea and the guidelines was to lower the cholesterol and only give them high cholesterol In this group of people with high inflammation and low cholesterol we had a 44% reduction in heart attacks and strokes, 63% reduction in heart attacks itself and, quite remarkably, a 20% drop in all-cause mortality.
Dr. Paul Ridker:
10:17
And it was really a real revelation.
Dr. Michael Koren:
10:25
So again to kind of fast forward again, between the years of, say, 1980 and 2010, cardiologists were making huge strides in reducing cardiovascular morbidity and mortality, and that curve has flattened In fact, maybe hasn't changed at all in the last 10 years, which is of great concern. So it leads to the idea that maybe we should be looking at other things, and this gets into some research that you and I are working on together as we speak.
Dr. Paul Ridker:
10:50
Well, that's right. So we learned during COVID that sometimes rates can actually go up, and that was a little scary. But I think you're right, Mike the constant decline the last 35, 40 years has really flattened out, telling us we now need to focus on some of these newer biologies. So what's been a lot of fun and again working with you has been great we're trying to figure out. Can we target this inflammation directly? Let's be a little careful there. JUPITER trial we talked about was giving a statin. It's a drug that lowers cholesterol and has anti-inflammatory properties. Could we give a pure anti-inflammatory drug to lower risk? We actually did a clinical trial called KANTOS, which used a very specific kind of inflammation inhibitor and it really worked really well. But that drug's not available, unfortunately, for our patients for some complicated reasons that actually had to do with cancer prevention.
Dr. Michael Koren:
11:45
So that's a molecule called canakinumab. Is that still used for certain pediatric arthritic conditions? I know it was briefly on the market for that.
Dr. Paul Ridker:
11:53
Well, it's still on the market for that. So canakinumab, which is another mouthful. These are drugs that are called monoclonal antibodies. They target a very specific piece of this inflammation pathway, and we showed it could lower the risk of a heart attack or stroke by about 15 or 20 percent, which is great, but the drug also has some great benefits in cancer, so it's being repurposed in the oncology community, and so we need to find another way of targeting this.
Dr. Michael Koren:
12:22
Sorry for that aside, just for our audience. One of the little tricks of the trade is if you hear a molecule or a chemical that ends with mab, it's a monoclonal antibody. So you can surprise your friends at a dinner conversation that you know the nature of their particular medicine.
Dr. Michael Koren:
12:39
So sorry about that.
Dr. Paul Ridker:
12:41
No, that's a great pearl, even for those of us who live in this world on a daily basis. So the question was could we find another one of these MABs that hits a different part of this particular immune system, and actually another mouthful? That drug turns out to be called Ziltivekimab, starts with a Z, and we designed a series of clinical trials, which are ongoing right now, using this particular kind of inflammation inhibitor which, by the way, is already commonly used. It's in a class of drugs that are commonly used to treat rheumatoid arthritis. Some patients take it to treat inflammatory bowel disease like Crohn's disease or ulcerative colitis. So the class of drugs has been around for 20, 25 years. We know it's pretty safe, but it's been used to treat classical autoimmune anti-inflammatory disorders. The trick is can we use it to actually improve outcomes for patients with heart disease disorders?
Dr. Paul Ridker:
13:45
Mike, there's actually three different clinical trials up and running using this Z drug, this Ziltivekimab. One we're going to talk about in particular is called HERMES, which is a heart failure trial. We're going to come back to that one, but the other two that are up and running. One is called ZEUS. I apologize for all these Roman and Greek gods, it's just the way we do it. ZEUS is a study of patients of ours who have chronic kidney disease, known atherosclerosis, and an elevated hsCRP. These are really high-risk patients. The good news is that trial is fully enrolled on a global basis. So right there, we're trying to get high levels of adherence and compliance and just bring that study home. The other one that's also starting is an acute heart attack trial. It's called ARTEMIS. We have a female goddess that time ARTEMIS is is really looking at acute heart attacks, people in the hospital with a heart attack, and what if we give this anti-inflammatory intervention on top of our usual care.
Dr. Paul Ridker:
14:41
But I think we're going to focus a bit on HERMES, which is, again it's a heart failure trial. That's a particular kind of heart failure. It's something that we call cardiologists call HEF-PEF, which is heart failure with preserved ejection fraction. What's that really mean? That means that your heart's pumping and it looks pretty good on a standard echocardiogram, but it doesn't work really all that well and you get the symptoms of heart failure shortness of breath, a feeling of congestion, a feeling of not being able to walk as far as you used to be able to, even though the heart seems to pump okay, but the heart's actually too stiff.
Dr. Paul Ridker:
15:23
I think that's the easiest way to understand what this is. And this is an exciting part of the heart failure world, because what we knew when I were in training, it didn't even exist. This again is this wonderful thing about medicine moving forward and science bringing us new ideas. And anyway, the bottom line is this HERMES trial, which is up and running all over the United States and globally, is looking for patients who have this condition called HFPEF, and they're going to get usual aggressive therapies. And when we do these randomized trials we don't want to deny anyone standard of care, so everybody gets the best care they can possibly get, whatever drugs your physician thinks are appropriate for you thinks are appropriate for you, and then we randomly allocate on top of standard of care. One arm gets a dummy tablet placebo and the other one gets the new drug, in this case this Mab.
Dr. Paul Ridker:
16:20
And it's really-
Dr. Michael Koren:
16:21
It's not a tablet per se, it's an injection.
Dr. Paul Ridker:
16:26
That's right. These are subcutaneous injections, kind of like people who might take insulin are pretty used to doing these. It's only once a month. It's a very small needle Really. I've actually had the dummy injection. It doesn't hurt very much at all.
Dr. Paul Ridker:
16:40
And you know, one of the great things, Mike, about clinical trials I always say to everybody is well. Sometimes patients say, well, why would I participate in this? Well, when we run our investigative meetings, and particularly when I talk to my own patients, there's an altruism involved here.
Dr. Paul Ridker:
16:57
I think medical progress is made by our patients. I really mean that. I mean the researchers tend to get the credit, but the reality is it's the patients who are doing the work. A patient who says, Mike, you're my cardiologist, I trust you. What do you think I should do? And it takes a pretty brave cardiologist to say you know, I'm not sure what to do. And if you trust me, let's put you into a clinical trial so that we can actually find out, using real you know methodology, is drug A or B going to be better for you? And I always say and for your children and for your grandchildren, because I think, at the end of the day, we all understand that we benefit from newer therapies that didn't exist 30, 40 years ago, because someone else did this for us and it's passing the baton in terms of health care.
Dr. Michael Koren:
17:50
Yeah, beautifully said. Thank you for that, and we like to talk about that as research, as a care option, and care is the human elements of what we do as physicians and as providers of these services, rather than treatment. So we don't know what the treatment is, but we can still provide care, and part of that care is education, is helping people understand their condition, and what we find in clinical trials and this gets back to Dr. Braunwald, who we'll talk about is that people in the placebo arms of clinical trials tend to do really well. In fact, I know you have a little story about that from Dr. Braunwald.
Dr. Paul Ridker:
18:32
Well, it's really important to think about. There's something in the epidemiology clinical trials world that we call the healthy cohort effect, which basically boils down to the fact that once you volunteer to be in a medical study, you actually do better than if you didn't volunteer, because what happens is, even if you get the placebo drug, you actually are getting more medical attention. You'll probably see the study nurse a few times more a year than you might see the regular nurse in practice. The physician involved in your care might see you more often, and the reality is there's just good things that happen when you get, as you say, care, even if it's not treatment. I think you're spot on with that.
Dr. Michael Koren:
19:10
Yeah, and Dr. Braunwald, for those who don't know him, is a world-famous cardiologist. He's well into his 90s. You know his exact age. I'm sure I don't know if that's a top secret or not, but he's been around for a long time, educating a lot of people, including both of us, and he was my attending physician at Beth Israel Hospital during my third year of medical clerkship and certainly influenced me to become a cardiologist.
Dr. Michael Koren:
19:37
And an organization that he started, called TIMI Group, was actually probably the reason I ended up doing cardiology, because I knew after medical school I was going to come back to New York for family reasons and I did a clerkship at Cornell New York Hospital and I saw a patient that was part of the first TIMI study in New York and I had seen the same type of patient in Boston. And this concept of doing research in multiple places and doing the same thing and then seeing a miracle of tombstones on an EKG go away with thrombolytic therapy was what ultimately sold me to become a cardiologist. And I know that you've had many interactions with Dr. Braunwald over many years and is a mentor and a friend of yours.
Dr. Paul Ridker:
20:20
Well, I owe Gene Braunwald my entire career, many times over. The greatest honor I will ever receive no doubt about that is having just been named the Braunwald Professor of Medicine. It means an enormous amount to me. Gene has been a mentor and a leader and a scientist for generations, a cardiologist His textbook is the one that we all have on our shelves. Gene's actually in his mid-90s and what's amazing to me is he is as sharp as ever. He will still call all of us on the phone with a very specific question, a very specific piece of information. Mike, he just gave cardiology grand rounds at the Brigham, like three weeks ago.
Dr. Michael Koren:
21:01
Oh, fabulous.
Dr. Paul Ridker:
21:03
It was just fantastic to hear him. He's a one of a kind. I can't imagine another one of a person like him coming along. I think part of the genius of his was A getting so many of us to become cardiologists. I know that you said you were heading into surgery and became a cardiologist because of Gene. I was heading into infectious disease, became a cardiologist because of Gene, and dozens of people have stories like that. His leadership skills were also phenomenal and he's just the biggest name in our world.
Dr. Michael Koren:
21:34
Well, thank you. Thank you for sharing that. So I'm also going to share a personal note with you, and you may not remember this and I haven't told you this ever, even though it's always been in my mind is again Paul and I were in medical school together. We knew each other well we weren't buddy-buddy, but we knew each other well and we played squash one time. Do you remember that?
Dr. Paul Ridker:
21:57
I played a lot of squash? Yeah
Dr. Michael Koren:
21:59
Okay. So we played squash at Vanderbilt Hall, which was the dorm at Harvard Medical School, and it was one time I think it was after lunch we played squash and I'm a decent athlete.
Dr. Michael Koren:
22:11
I played varsity tennis in high school. I took up squash senior year in college and I was playing it in medical school and I was, frankly able to beat most people that I played just being relatively fast and athletic, et cetera and I played Paul I had never played him before and we just said let's play some squash and you absolutely kicked my ass, you absolutely destroyed me and I learned that you could be a really good athlete and you think you have certain capabilities. But unless you have a plan, you're not going to be as good as you could be and what I learned from you in squash is that you had a plan on every single point, and there was a great learning lesson for me, not only about squash but about life, and I appreciate that. And I also think that is relevant to what we do in clinical research, because we do everything by a protocol. We have a plan and within that plan, we create knowledge and that knowledge can be shared with the people that are part of the plan.
Dr. Michael Koren:
23:13
So, again, I encourage people to do clinical research and they have all these ancillary benefits that are really, really important. And one of the data points that I like to share with everybody is the fact when you ask somebody that's never been initiated in a clinical research environment, has no idea what clinical research is, and you ask them, would they be willing to do a research study, only about 30% or 40% say they're very interested in doing something like that. If you say that their doctor recommends it, that goes up to 50%. But when you ask a patient that has completed a clinical trial if they would do a second clinical trial. 97% to 99% of people said they would do a second one. So what product can you think of where
Dr. Michael Koren:
23:56
there's such skepticism before you're exposed, and then, after you've had the experience, you say sign me up for the next one. So I think that's a remarkable testimony to what we do day to day.
Dr. Paul Ridker:
24:07
Mike, I actually added two more caveats to that. Sometimes we do what we call secondary prevention trials. These are studies of patients who've already had a heart attack or already had a stroke or maybe had bypass surgery and angioplasty. Those are much easier. Patients who've actually suffered an event really understand the limitations of medical practice. When you do a primary prevention study someone who is healthy that's tougher because those individuals think I'm immortal. I've never been sick. Why do I need to be in this study? And I think that's a really interesting thing.
Dr. Paul Ridker:
24:42
You mentioned something else that's really smart, which has to do with language. Now, both my kids I think you know this are one writes for television, one writes novels. I didn't get anybody to go into medicine. That was my biggest failure in life. But language really matters.
Dr. Paul Ridker:
24:58
When we do our clinical trials, we also want to make sure we enroll a real cross-section of the people who might ultimately benefit from the drug. So that means we have to enroll minority participants. We have to enroll people who might not have access to care as easily. We emphasize making sure we enroll large numbers of women as well as men, and I've learned over the years that language really matters. So we have a problem here.
Dr. Paul Ridker:
25:21
When I'm trying to enroll inner city populations, the words that we use principal investigator ooh, that sounds like a police officer to people. When we talk about clinical trial, that sounds like going to court to some people. So we have to actually change our lexicon and say this is a medical study to benefit your care and your health and change the way we actually use the words, because if we don't do that, we're not going to be able to enroll everybody. And again, one of the ethics of clinical studies is that whatever risk there might be needs to be shared equally by all the people who might benefit. That's just a fundamental thing about ethics 101. Yeah.
Dr. Michael Koren:
26:07
Yeah, I love those comments and to add to those comments, I would say that I like to remind people that when you write out principal investigator, you spell it P-A-L. The principal investigator is your pal. We're not investigating principles, we're not philosophers or passing judgment on anybody, so sometimes that helps break down the exact issues that you're talking about with language. So the principal investigator is your PAL, P-A-L. So that's always a good thing to remind patients about. But really, really well said. Paul, this has been an absolutely delightful discussion. Thank you for educating all of us about inflammation and vascular disease. Thanks for talking about the HERMES study and we're really excited to continue the enrollment in the study and to learn more about the inflammatory hypothesis and how we can make a difference in patients' lives. So thank you for being part of MedEvidence!
Dr. Paul Ridker:
27:03
Mike, it's great to reconnect with you. You've done a great job. I can't wait to listen to other episodes of Truth Behind the Data, and this has really been a lot of fun.
Announcer:
27:12
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