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IRA FLATOW, host:

You're listening to Talk of the Nation Science Friday. I am Ira Flatow. Next, an intriguing and controversial health study, a study found about Crestor which was usually prescribe to lower cholesterol. It could be beneficial even to people who would not normally take it. Is a new drug that hasn't been out that long. To setup the clinical trials, the doctors ruled out volunteers who had signs of serious heart disease or cholesterol levels high enough to merit treatment with Crestor under current guidelines. They selected only study participants who've had (unintelligible) levels of something called high-sensitivity C-reactive protein or CRP, a marker for inflammation somewhere in the body.

And at the end of the trial, what doctors found that a group of patients taking Crestor suffered fewer heart attacks and strokes and ultimately fewer deaths. Should Crestor and other statin drugs like Lipitor or Mevacor be prescribe routinely then to people who show high levels of high-sensitivity CRP to lower their risk from heart attack or stroke, and if so, what about their potentially dangerous side effects? That's what we'll be debating this hour at the moment with my next guests.

Our first guest is an author of the study of this week in the New England Journal of Medicine. Dr. Paul Ridker is professor of medicine in Harvard Medical School, director of the Center for Cardiovascular Disease Prevention at the Brigham and Women's Hospital in Boston. He is one of the author of the study which was funded AstraZeneca, the maker of Crestor. He joins us from the studios of WBUR in Boston. Welcome back to Science Friday, Dr. Ridker.

Dr. PAUL RIDKER (Professor, Harvard Medical School): It's a pleasure to be back here with you, Ira.

FLATOW: You're welcome. My other guest was not involved in the research but he wrote the accompanying editor which urge a bit of caution interpreting the results. Dr. Mark Hlatky is a professor of health research and policy and professor of medicine at Stanford in Stanford, California. He joins us from our studios on the campus there. Welcome to the show.

Dr. MARK HLATKY (Professor, Health Research and Policy, Stanford University): Thank you, Ira. I am glad to be here.

FLATOW: You're welcome. Dr. Ridker, let's go over the trial results in a little bit more detail. Can you fill it in for us a little bit?

Dr. RIDKER: It's pretty straightforward at one level. We as cardiologists believed that we should treat patients with high cholesterol because they are at high risk, and we've learned over the years that you really do want to lower your cholesterol if you're a high-risk patient with high cholesterol and these statin drugs are very effective in doing so. The problem of the whole field has been that about half of all heart attacks and strokes that occur among - not really patients but we have to call them healthy individuals in society, about half will occur on people who actually have low levels or average levels of cholesterol.

So we setup this trial to only look at people whose levels of bad cholesterol, the LDL cholesterol, were already below, not just the threshold for starting these drugs, but below the threshold for treating. So no one in the study has an indication for the statins, but they did have an increased level of hs-CRP, this marker of inflammation. We randomized almost 18,000 people in 26 different countries and the trial was supposed to run for another two and a half years, but the Data and Safety Monitoring board recommended that we stop the trial a few months ago because we had a remarkable finding. The rate of new heart attacks was down 54 percent. The rate of stroke which can be quite devastating was down 48 percent. Bypass surgeries and angioplasties, very expensive for society, those were down 47 percent, and perhaps most remarkably because it really hasn't been seen when we give statins to high-cholesterol patients, a 20 percent reduction in all-cause mortality.

So it's really quite striking. There is also issues about how efficient is this approach? There is something called the NNT or number needed to treat, and it's a metric that we use to figure out, well, is this something we can afford as a society and how is it going to fit in? That number was only 25 over a five-year period. And what's remarkable to steering committee is that value is actually less than the value what we currently have for people of high cholesterol in this setting. So it is really a remarkable finding, and I think we'll change - or at least we have to think about changing the we practice medicine.

FLATOW: Does this say to you that the CRP is more important than screening people for risk of heart attack than their cholesterol level?

Dr. RIDKER: By no means. If your cholesterol level is high, and you have some other risk factors, you are a higher-risk patient and we know overwhelmingly that this class of drugs, these statins are a safe and effective way of lowering that risk, assuming of course, that we first dealt with diet and exercise and smoking cessation. This is by no means a replacement or change of policy at that end. The problem is what about all the people who have low levels of cholesterol who we know from the biology of this disease.

Remember, we have 20 years of elegant vascular biology telling us that inflammation, the process by which our bodies is fight infection, deal with things going wrong, can get reflected by the simple blood test, the hs-CRP. Twenty or thirty studies around the world have shown that if you got an increased level of this, you are at higher risk. The question has been what do we do about it? And now, we have some evidence that, well, a simple and safe therapy seems to dramatically lower that risk.

FLATOW: What's wrong with that thinking, Dr. Hlatky?

Dr. HLATKY: Well, let me say a few things. First, I want to congratulate Dr. Ridker on this important study. I mean, the amount of work that goes into doing a study of this magnitude with 18,000 patients and years of work is tremendous. So I think it's a very important study. I think the question always in looking at studies such as this one which because it's so big and it is very difficult to do - to replicate, to do over again. So the question is not so much what happen to the people who are in the trial but what are the implications for the rest of us who are not necessarily represented in the trial. And I think that there is a couple of things, if I stand back and look our society as a whole, we know we have a epidemic of obesity now and diabetes that perhaps the trends in reducing cardiovascular mortality are going to reverse because of these kind of problems.

And my own feeling is we need to address the root causes of that epidemic with measures such as better diets and so on before we use as a first step taking a drug. And so, I think if you look at the big picture, I think we need to emphasize healthy behaviors and healthy lifestyles and for some people, quite frankly, it's a little easier to take a drug than it is to change their behavior. So I think that's the big context for this.

The other thing I would say is that Dr. Ridker has, in his good results, emphasized this relative-risk reduction, which is quite impressive at about 44 percent, but for your personal decision-making about whether to take the drug, what you really need to see is what would my rate of events be if I didn't take it and what would the rate of events be if I did? In order to estimate how much benefit you get from taking the drug. And it's important to emphasize that everybody in Jupiter had different levels of risk. The underlying levels of risks varied across the different groups of patients who were in that trial.

And so, for making a decision for an individual person, what you'd like to know is what is my risk if I didn't take it? What is the risk if I did? If I have high risk, it's more beneficial to me to take this drug because the chance of any adverse events is pretty much the same for everybody. It cost the same to you about $100 a month no matter whether you're a high benefit or low benefit. So for all of those reasons I think that we need to be a little cautious. We need to do due diligence on the study. I do think it's, again, a landmark study and I congratulate Dr. Ridker on his accomplishment.

FLATOW: Dr. Ridker, would you suspect that the other statins yours competitors in this one, Lipitor, Mevacor, other ones would also show the same results?

Dr. RIDKER: So there's a number of issues. These are all very good ones. We'll start with the question you just asked about other statins. My own research group showed more than 10 years ago that a different statin, Pravastatin, also lowered CRP as well as cholesterol, and at the benefit of being on that statin was greater. The relative reduction that Dr. Hlatky was currently talking about was greater among those who have this increased CRP. In fact, my own research has shown that for all the statins, that they have this interesting phenomena there what we called two-fer drugs, they both lower cholesterol and they lower this inflammatory process.

That being said, the magnitude of benefit that we saw here was unexpected. It's almost twice the benefit we see when we give statins to patients with high cholesterol. So that may suggest that the more potent the statin, we know that's a more potent effect for LDL reduction and as a more potent effect for CRP reduction. So, while yes, I think it's a class affect in one sense, I think the magnitude of benefit we saw here reflects a very potent drug Crestor that we use. It think we kind of hit the sweet spot by selecting people with a high hs-CRP and then hitting it with a very powerful drug.

FLATOW: But the statin, well, let me just, interrupt for a second. The fact that Crestor sponsored this study, does it influence your data in one way or the other?

Dr. RIDKER: Oh, no. This is a randomized double-blind, placebo-controlled trial. There is no way the sponsor can actually deal with it. In fact, it's interesting, Dr. Hlatky and I both work at very academic medical centers. We held the data here in Boston. The company actually, interestingly enough, never had access to the unblinded data until after the steering committee had written their manuscript and submitted it for publication. It's about as tight a fist as you can hold in this setting.

FLATOW: Mm-hm. Let me get a question in here from - coming in on Twitter from AzizHP(ph), says, can the data from the study be reanalyzed separately for each risk group?

Dr. RIDKER: The answer is yes, and Dr. Hlatky raised this appropriately. And I want to agree with Dr. Hlatky, actually, on a major issue. He's right. The first step here is going to be lifestyle. We have shown, as have others, that going to the gym, throwing out the cigarettes, is a terrific way to lower vascular risk. That's the most important issue. And it also does lower CRP. So, I agree on the lifestyle side. It's just that we've been frustrated. A lot of our patients have a tough time doing that.

But the question about different risk, absolutely. So, certain groups in the study, like, for example those with an increase Framingham risk score - this is a scoring system we use if you had a little hypertension, a little smoking; it's more efficient there and somewhat less efficient if you're didn't - but one of the most remarkable findings here was we had about 6,500 individuals who have an increased level of hs-CRP and no other major risk factor according to our current guidelines, and that group got approximately a 40-percent reduction. It says to us that this inflammatory process, which we can't feel, we can't tell, we don't do well, is driving off a lot of this.

FLATOW: And so why then are we still emphasizing - I'll only play Devil's Advocate here for a second - if this has such a - is such a good predictor, why are we still worried about cholesterol levels?

Dr. RIDKER: Well, cholesterol remains a very important factor, and they're different. You can have a...

FLATOW: I mean, but here you have these people with low cholesterol levels with the high CRP level, and they're at great risk of heart attacks, yet we still keep emphasizing the cholesterol levels.

Dr. RIDKER: Well, we have to step back and remember the biology. If you have low cholesterol and a low hs-CRP, we have no evidence these drugs are effective. In fact, we did a big pilot study in that group and we saw very low event rates and no efficacies. So, there's a large part of society that should not consider these drugs. If you have a high cholesterol and other risk factors, we already know they work. In order to get this process, the heart attack or the stroke, it seems that the cholesterol levels tell us how much plaque is building up in your arteries.

The inflammation is telling us like the likelihood that plaque rupturing. And that rupture process is what shuts off the oxygen to your heart or to your brain, causes that heart attack and stroke. So, the biology has shifted. We now teach the Harvard Medical students about atherosclerosis in a very different way than Dr. Hlatky and I were taught. We now teach the students it's a disease of cholesterol and it's a disease of inflammation.

FLATOW: Mm-hm. Any comment, Dr. Hlatky? You agree with basically that?

Dr. HLATKY: I think that there's a couple of things to say. One of them is I do think that cholesterol is still probably the most important thing that we are dealing with here, partly because (unintelligible) to be involved in the cause. I do think that the inflammation is involved as well. CRP is a marker for that inflammatory process. It's not as clear to me that it's as related in terms of cause and effect as the cholesterol. But I do think that we have a better understanding of the overall process.

And the other thing I'd say is that, as Paul just mentioned, you know, there are these hygienic measures, the good lifestyle things that we talk about, do have an effect on these things, too - the CRP and the LDL - and we - and I think that's the foundation for further treatment. And yes, there are some people who should go on a drug because - despite their (unintelligible), they can't get these things under control.

FLATOW: Let me just interrupt to say this is Talk of the Nation: Science Friday from NPR News. Yes, I'm talking with Dr. Paul Ridken and Dr. Mark Hlatky. Go ahead, Dr. Hlatky. Did you want to finish a thought there?

Dr. HLATKY: Well, I think one of the other questions is that, you know, which patients should be taking this? Which ones should go on the drug? Which ones should get their CRP tested? And one of the issues in generalizing always is to look at who is in the study and maybe who wasn't as well-represented. I mean, if you look at me personally, for instance, I might be a candidate for Jupiter, because my...

FLATOW: What is Jupiter? What is Jupiter? The planet, I know that.

(Soundbite of laughter)

Dr. HLATKY: This is the study - yes, yes, yes. That was the last segment on the stars.

(Soundbite of laughter)

Dr. HLATKY: But this is the Jupiter trial.

FLATOW: I see.

Dr. HLATKY: And the thing to say is, the average age of the patients in the trial was 66. You know, I'm a lot younger than that. You know, the average body mass index in this study was 28. Mine's about 21. You know, it's a lot lower. The average cholesterol was about 108. You know, mine is about 90. So, you know, how well do the results of the study, you know, apply to people like me? I think that Dr. Ridker has just had the opportunity to present the first results, the headlines, from his study, and I'm sure that he and his group will drill into these data in a deeper way to give us more details about how things turned out for different groups of patients. And so, we can see the actual rates of events. Yes, the relative risks went down into different groups, but one of the things I'd like to know is, well, how much benefit would it actually give to somebody like me?

FLATOW: Yeah.

Dr. HLATKY: My risk is much lower than the average person in this study, and so, I probably wouldn't get as much benefit from the treatment as those people did.

FLATOW: Right.

Dr. RIDKER: I can actually answer some of that for Mark right now. We've done some of these analyses. It's quite interesting. So, while Mark is actually correct that the average person of the study was overweight, 25 percent of this Jupiter trial have a BMI, the body mass index, that's less than 25, a value that we consider pretty reasonable. And that group got the same absolute as well as relative risk reduction, which is interesting. It says it's not about obesity; it's about some other phenomenon.

We have men over 50 and women over 60, but there's two groups, Ira, that I'd like to emphasize that really have been just excluded from prior clinical trials in general. We enrolled nearly 7,000 women. Women have just not been in prevention trials for statins before. That group got the exact same reduction as did the men and fascinating to us, their absolute reduction is almost the same, even though we usually anticipate that women are at lower risk. And the other group, one that I'm very proud of - we randomized almost 5,000 minority patients - black and Hispanic patients. And in order to that, it required going to communities across the United States that, frankly, we often don't go to do clinical trials. It required having my minority investigators and minority nurses working with us.

We went to South Africa and Mexico to accomplish this. And for the first time, we have evidence in minority patients, yes, indeed, statin therapy is highly effective. So, this public health (unintelligible) there are a variety of levels. That all being said, Mark is correct. I think we have to always step back, figure out how it applies to the average patient and get us more of big picture. I would argue - I run a center of cardiovascular disease prevention. and I agree with the first level. It's got to be, hey, diet, exercises, smoking cessation, but we now have what's called an evidence-based paradigm, a shift in our thinking.

FLATOW: All right, Dr. Ridker. Hang on a sec - for a second. We have to take a break. We'll come back and talk about some more with Dr. Paul Ridker and Dr. Mark Hlatky about the study. Stay with us. We'll be right back.

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FLATOW: I'm Ira Flatow. This is Talk of the Nation: Science Friday from NPR News.

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FLATOW: You're listening to the Talk of the Nation: Science Friday. I'm Ira Flatow. We're talking about the recent Crestor study and heart disease with Dr. Paul Ridker, who is at Harvard Medical School, and Dr. Mark Hlatky, who is at Stanford University in Stanford, California. Let's see if I can get a phone call or two in here before we have to go. Toni in Evanston. Hi, Toni.

TONI (Caller): Yeah.

FLATOW: Hi.

TONI: Hi, hi. You know, this has been very interesting week because two days ago, somebody had presented the study on - the actual study on statins, and I was hoping this conversation was going to happen. I have so many things to comment on, but one is, I'm a physician. I have been doing - getting a CRP and a density profile of cholesterol in all my patients in their initial lipid screening, not just a level.

And I'm surprised that the density haven't come up in this conversation, because what I find is that people with high CRPs, unless they're elevated from an acute infection going on or possibly an autoimmune disease, it's almost always associated with this - with LDL. And if you look at the research, it's the small, dense LDL that's the problem. It's not that LDL is bad cholesterol, which is what we hear all the time. You know, LDL is your bad cholesterol and HDL is your good cholesterol, and that's really simplifying and not exactly the truth. The truth is that small, dense LDL is problematic and there's many people who walk around a with a normal or low cholesterol level who have small, dense LDL.

FLATOW: So, you're saying the CRP is not what we should be study - looking at?

TONI: No, CRP is - we - absolutely. CRP is inflammation, period. It's inflammation, and we all know that inflammation increases your risk for all kinds of things, including cancer, not just heart disease, diabetes. It's associated with it. But what usually gets your CRP to be elevated outside of an acute infection or an autoimmune disease is that there is small, dense LDL. The same mechanism that causes that small, dense LDL usually causes this elevated CRP. Every doctor should be doing a small, dense LDL and CRP.

FLATOW: Dr. Ridker, any comment on it?

Dr. RIDKER: Yeah, I'm afraid I'd have to disagree. While it's anecdotally the case sometimes that these track together, I can tell you in very large studies involving tens of thousands patients, in fact, the relationship between hs-CRP and various forms of LDL, and that caller is talking about small, dense - it's actually rather weak. It's also important to point out that large studies have been done demonstrating that the best lipid measure remains the total HDL cholesterol ratio, which is very inexpensive. So, in fact, despite running a complex lipid prevention center here in Boston, I must say, we actually don't use what is called the advanced lipid testing on a broad basis at all. We limit it to a very small number of patients.

FLATOW: You're talking about high-sensitivity CRP. Is that different than the CRP everybody is talking about?

Dr. RIDKER: Yes and no. The clinical test you have to send for the purposes of measuring inflammation and cardiovascular risk or risk of diabetes is the hs-CRP test. There is a second test called regular CRP. They measure the same protein, but in a very different way, and the regular CRP test simply can't give you the values you need in this very low range that cover the issues we're talking about here today. So, in a physician's office or in a - for a patient, it has to be the hs-CRP.

FLATOW: Now, you're one of the co-inventors of the CRP diagnostic testing. You currently hold the patent for it. Correct?

Dr. RIDKER: That's correct.

FLATOW: So, do you see the - how do you see down the road measurements of the c-reactor protein being used?

Dr. RIDKER: Well, it's very unclear. I think that my job as a scientist and a clinician/investigator is to find out what works, set up experiments that help us to understand, does it pick up risk? You know, 30 investigators worldwide have replicated our data in cohorts all over the world. So, we know the hs-CRP predicts risk. This trial was set up to find out whether we can do something about it. But I think individuals who write guidelines and sit down have to consider that evidence.

FLATOW: Let me ask you. If inflammation is the boogy man here or good part of the boogy man, why not develop a drug that attacks the inflammation directly instead of having the statins do it? Or was that a better class of drug to do it?

Dr. RIDKER: Fantastic question, Ira. So, this is the future of where medical therapy is going within the vascular-biology community. Let me take a second here. The statin drugs, I think, historically we'll just end up being lucky. They both lower cholesterol, and they lower inflammation, and we've been blessed with them because they seem to be so safe. We'll put that aside. You're right. The next step is, can we design drugs that inhibit this vascular inflammation, but without also affecting cholesterol or how our blood clots? And in fact, there are many novel drugs in development that have this property. Some of them are being used to treat arthritis. So, they already exist, these drugs, that we typically have given arthritis patients, and we're trying to put together now something called the cardiovascular inflammation-reduction trial to directly address your question. Can we give a certain kind of drug that inhibits inflammation, but given on top of a statin, on top of the aspirin, on top of the other things we already do? And then find out, does inhibiting inflammation, per se, benefit or not? And if it does, we'll have a whole new direction to go to prevent this very deadly disease.

FLATOW: Well, we've run out of time. I want to thank both of you joining us this hour. Dr. Mark Hlatky is a professor of health research and policy and a professor of medicine at Stanford University in Stanford, California. Paul Ridker is a professor of medicine at Harvard Med School, director of the Center for Cardiovascular Disease Prevention at the Brigham and Women's Hospital in Boston. Gentlemen, thank you for taking time to be with us.

Dr. HLATKY: Thank you, Ira.

FLATOW: You're welcome.

Dr. RIDKER: It's a pleasure.

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