Controversies in Lipid Management
Controversies in Lipid Management
Dr. Hutter: Hello. I'm Dolph Hutter. Welcome to the American College of Cardiology, Conversations with Experts. In this program we will discus statins and inflammation. With me today is Dr. Paul Ridker from the Brigham and Women's Hospital in Boston.
Dr. Ridker: Pleasure Dolph.
Dr. Hutter: Dr. JoAnne Foody, from the Brigham and Women's and Faulkner Hospital in Boston.
Dr. Foody: Glad to be here.
Dr. Hutter: And Dr. Rob Calif from Duke. Thank you all for joining us. Now first of all let me just throw out some different topics. You know we heard the word pleiotropic effects of statins. We're not going to talk about LDL lowering. That's pretty well summarized. Pleiotropic effect, what does that mean? Paul, what does that word mean?
Dr. Ridker: Well if I probably had my way I'd get rid of the term pleiotropic really. Pleiotropic to me means a drug has many effects throughout the body, but that's true for every drug I prescribe. I think what we're more interested in are their on-target effects - in the case of statins on lowering LDL cholesterol - and are there other effects that might or might not be beneficial for the patient.
Dr. Hutter: Okay.
Dr. Ridker: I prefer that kind of context than Pleiotropic.
Dr. Hutter: What do you think JoAnne? Do you think it's a misnomer?
Dr. Foody: Absolutely. I think that this pleiotropic really has...it's very hard for people to understand. I think we really need to focus on the on-target, as Paul has said, the lipid-lowering, LDL-lowering effects, as well as potential other effects that may be beneficial.
Dr. Hutter: Rob? What's your take?
Dr. Califf: My insight into this is coming from being able to now look at genomic technologies, something Paul has been doing for awhile, but when you look at the effects of a drug on let's say gene expression, there can be hundreds of genes effected. If you look at metabolomic profiles you're finding a lot of activity that occurs at distant pathways, biologically, than we were even thinking about. So I think most of the world now is moving to this concept. On-target means you developed the drug for a reason and you want to measure, Are you affecting that mechanism? And then you're looking throughout the whole universe of other biological pathways where undoubtedly a lot is happening with every drug that we ingest systemically. We don't know the meaning of most of it, but we're beginning to learn about it.
Dr. Hutter: Yeah, that's a very good point. I guess when you go back to aspirin, you know the "pleiotropic" effect was just a different effect than for what it was initially used. So we can get rid of that word do you think? Good. Because it took me a long term just to learn how to spell it, so at least I don't have to remember that anymore.
What about antiinflammatory effects? Are there any...statins have any role in antiinflammatory effects?
Dr. Califf: Well you know I'd say there is definitely an antiinflammatory role if you measure a marker like CRP, which is one of the markers for inflammation, it goes down with statins (Figure 1). The questions are what does it mean? Just defining inflammation, it's a fairly broad term and it means a lot of different things are going on. As a clinical trialist, what I'd say is measure things, they change, it means something is going on. Understanding it takes a lot of empirical research. The clinical meaning of this is complex and we'll sort out by measuring things like what's the mortality rate, and what other clinical phenomena occur when you take a statin or don't take one.
(Enlarge Image)
Figure 1.
Average Change in CRP by Study Characteristics
Dr. Hutter: All right. JoAnne, so you think that statins right now, which is the primary for LDL lowering and not for antiinflammatory action?
Dr. Foody: Well, I think as Rob said, that the real issue is that we see that statins lower markers of inflammation. The question is whether that's due entirely to the LDL lowering effect and thereby causing that as a biomarker? Or if that's something unique with statins. I tend to believe that the majority of that effect is due to the LDL lowering.
Dr. Hutter: Okay.
Dr. Foody: And that we see that parse out that way.
Dr. Hutter: I want to save you for a little bit later, Paul, because I'm gonna ask you specifically about CRP, but Rob...let's go back to this little question. Is most of the beneficial effect defined by the lowering of the LDL? Or is there a fair amount that we can't explain? You said 70% is related to the LDL lowering per se?
Dr. Foody: Well I didn't give a number, but if we look at meta-analyses...
Dr. Hutter: I guess that's something I have read about, you know, but...
Dr. Foody: If we look at meta-analyses you see that the predominant component is related to the reduction in LDL. And that's debatable. I'm sure Paul will have a comment.
Dr. Hutter: What do you think about that, Rob?
Dr. Califf: Yeah, I'd say this is always an impossible question to really answer. But if you draw a regression line through the lowering of LDL and the clinical benefit, there is a nice relationship. But that doesn't tell you for sure that the LDL lowering itself is a direct mediator, it just tells you when it's moving things get better. And it's moving could be an indicator that something else entirely different is going on. So if I had to bet, I'd say it's LDL lowering based on what we know.
We're doing a kind of an interesting study funded by the NIH in teenagers with lupus randomized on statins or placebo. Their LDL's are not very high, but they get atherosclerosis, or something that looks like atherosclerosis. So we'll be having those results actually in just a year or so. That might give us some insight.
Dr. Hutter: And there is also data from the non-statin literature that lowering of the LDL is beneficial. I mean, Paul, I mean there is a lot of data about that in terms of other ways of lowering the LDL, including such things as diet, plasmapheresis, and things like that. There are clinical studies that have indicated that the LDL is a very important target. Would you agree with that?
Dr. Ridker: Absolutely. So if we look at this broadly we know that diet is a terrific way to lower heart disease risk, and yes it lowers LDL. The POSCH trial showed us that ilial bypass lowers LDL and that seems to be good. The tension has been there's other drugs that lower LDL that haven't been so good. Post-menopausal HRT is a classic example of a drug that lowers LDL raises HDL, and didn't do a very good thing. For me it's of interest because it's a drug that happens to raise CRP, so it's an interesting question. Torcetrapib was a problem for us.
Dr. Hutter: Yeah.
Dr. Ridker: Very good LDL-lowering drug, terrific HDL raising drug didn't work so good.
Dr. Hutter: It not only didn't work so good and it caused some harm.
Dr. Ridker: That's right. So the tension here is, as we've been talking about, is it the statin - because that's what the trials tell us - the trials tell us if you're going to take a drug, the statins are extraordinarily good at lowering the risk of heart attack, stroke, cardiovascular death, and it happens to lower LDL. I would probably argue, and it happens to lower CRP, and isn't that interesting. That this drug does two things in my mind that are very effective, but we know that at the end of the day from my practice largely for those patients who can take the drugs, that's my first choice because I know from the trials that's what it does.
Dr. Hutter: All right. Now, let's move on to CRP and then...and I know you've been doing some studies and you've given us some information about CRP. What is the past information about the role of CRP? Let me first ask you, Paul. Is CRP an adequate marker of "inflammation?" I mean, is that as good as anything else? Is it a good surrogate marker? What does it mean? Do you think CRP is a good valid indicator of inflammation?
Dr. Ridker: It's wonderful question, and in some ways, the problem is that when we published our first CRP paper, which is now 1997, I would have hoped that this many years later we'd have a better marker of inflammation. We don't....
Dr. Hutter: Yeah.
Dr. Ridker: That's in some ways perhaps a disappointment. But also it maybe just says that what you're really after is a surrogate marker of this process. That does not mean that lowering CRP per se is a target. That's the tension in this field. It does mean inflammation seems to matter. Most inflammatory markers give you a similar sense of what's going on. The problem in this field has been, yes, if you've got an elevated CRP for probably any reason, risk of a heart attack or stroke is high. That's true in primary prevention; it's true in secondary prevention. In the statin arena, as Rob pointed out, these drugs lower CRP. And we've done some analyses of completed trials like AFCAPS/TEXCAPS which suggested that there was benefit in people who had a lowish LDL and a high CRP, within PROVE IT (PROVE IT-TIMI 22 - Lipid Lowering Results) and A to Z (A to Z - Phase Z), the demonstration was shown that if you not only get the LDL down below an aggressive target, say of 70 mg per deciliter, but also got the CRP down below a target of about 2 mg per liter, the patients seem to do better (Figure 2). And that's a clinical thing though, it's not necessarily...
(Enlarge Image)
Figure 2.
PROVE IT-TIMI 22: Cumulative Incidence of Events Based on LDL or CRP Levels Achieved with Therapy
Dr. Hutter: Well they definitely did better, didn't they? I mean, statistically they did better.
Dr. Ridker: Well they clearly do better. We're not quite sure why they do better.
Dr. Hutter: Gotcha, okay.
Dr. Ridker: And so the tension at the research end is why, the clinical end is, Hey, they did better, why wouldn't you want to be in that low CRP/low LDL group. And so this notion of dual goals has become a relevant question. But all that being said, as Rob correctly would point out, you need a fundamental endpoint trial to test all of this.
Dr. Hutter: Interesting that you should both mention that, and all three of you have mentioned that. Is there an endpoint trial in progress? Would you like to comment on that possibility.
Dr. Ridker: Well, yeah, so with help from the NIH and investigators around the world, in 2003 we launched a very large clinical trial, called JUPITER. JUPITER is pure primary prevention, so it's healthy, middle aged men and women. They don't qualify for a statin. That's the key. They have an LDL cholesterol in primary prevention of less than 130, but they've got a CRP above 2. So they're in this high risk group.
Dr. Hutter: So what is their average lipids? I mean what is the average of the population? Is it like at 115? Or 100? Or 90? Or what?
Dr. Ridker: Well, we randomized nearly 18,000 patients around the world in this trial. The average LDL on the weigh-in is only 104.
Dr. Hutter: Wow.
Dr. Ridker: And the HDL is 51. So these are not folks...
Dr. Hutter: A lot of people wouldn't treat those people.
Dr. Ridker: I must say in my own practice I wouldn't.
Dr. Hutter: Yeah, yeah. But they all have CRPs of over 2?
Dr. Ridker: That's right. The CRPs are over 2. The average is around 3-1/2 to 4, and half are getting rosuvastatin and half are getting placebo, and the question will be was that a good idea or not?
Dr. Hutter: Rosuvastatin in a high dose? Or a moderate dose? Or...?
Dr. Ridker: We actually elected to go with a pretty high dose.
Dr. Hutter: Okay.
Dr. Ridker: 20 mg.
Dr. Hutter: 20 mg.
Dr. Ridker: The idea being let's dramatically lower the LDL, let's dramatically lower the CRP, and see whether that's beneficial or not.
Dr. Hutter: Now how are you going to know? Rob, weigh in on this because you're a well established trialist: How are you going to know which it is? How do you differentiate that if you get the CRP down to 1, got the LDL down to 40, which is the beneficial effect?
Dr. Califf: Well why do you care so much I guess would a question I would ask. I mean...
Dr. Hutter: Well, okay.
Dr. Califf: If I were a patient, and I said okay, you know it's interesting to know what my biochemical measurements are. What I really care about is am I gonna have a stroke, and am I gonna die, or have a heart attack. And if Dr. Ridker can tell me, based on this trial, people like you have a much lower risk of having a heart attack or a stroke, that's the main thing. That's what the rest of us like to argue and discuss.
Dr. Hutter: Well actually not...you know I see a lot of patients come in and say, you know, "My LDL is 69, Doc, or 68 and I feel well. I'm getting little muscle aches, I really don't want to push this dose, do I really have to, Doc?" And somebody will say "Well let's check your CRP? If it's 5, then yes you have to." I think it is a practical question because there are a lot of patients where you don't want to push it or you can't push any harder, and should you really try to push. So, I think it does make a difference whether or not it's the CRP or the LDL.
Dr. Califf: It still doesn't tell you which it is, because the drug's going to lower both, even in the range that Paul is talking about.
Dr. Ridker: So I would say that Rob is correct about this. This trial was designed for public health. This trial was designed to say, are there a lot of people who...
Dr. Hutter: Good point.
Dr. Ridker: ...just don't have high cholesterol and therefore we're not giving these drugs because we're wed to a biomarker who have a high CRP so risk is up. Will they benefit.
Dr. Hutter: Okay.
Dr. Ridker: So the question would be, what if JUPITER is positive and what if JUPITER is negative. If it's positive, I agree with Rob. The problem is a situation where we say in a very practical sense, if your CRP is elevated you probably would be on these drugs if it's cost effective, and the usual kind of things. There is safety information here as well. We're putting, you know, half of these 18,000 people on a dose...
Dr. Hutter: Right. Yeah.
Dr. Ridker: ...that's going to drive the LDL to 40 or 45? We need to see if that's safe. The pathophysiologic question of is it inflammation reduction or is it lipid reduction is actually going to require another trial.
Dr. Hutter: Okay.
Dr. Ridker: And we're actually talking to the NIH about how to do that with target antiinflammatory agent, rather than a statin.
Dr. Hutter: Oh, well that'll be interesting. That will be interesting. So, are you going to be able to say...by the way, this trial is going to be done in another year or so do you think?
Dr. Ridker: JUPITER is an endpoint driven trial which means that it's over when it reaches a certain number of endpoints. When the...
Dr. Hutter: Oh, so you don't know exactly how long it's going to go.
Dr. Ridker: That's right. we're guessing another year, year and a half.
Dr. Hutter: Okay, good. So at the end do you think you'll be able to say...well, you make a good point. This is a epidemiological question. People with this thing ought to go on it. But you won't be able to tell us how far we should push the CRP or the LDL, is that right? The trial isn't designed to do that. Is that what you're both telling me.
Dr. Califf: I've talked to Paul about this. I'd love to hear what JoAnne says about how much you can infer by looking at post treatment values about prospective targeting.
Dr. Hutter: Yeah. Yeah.
Dr. Califf: I'm nervous about it.
Dr. Foody: Well, I agree...
Dr. Hutter: Well, it sounds to me like you can't even answer the question, but let's see what...
Dr. Foody: Well, no, but you can answer the question of what the utility is of defining through CRP in an otherwise low risk population whether there is an advantage of using a statin.
Dr. Hutter: Okay.
Dr. Foody: You certainly can't make inferences around underlying pathophysiology in relation of inflammation, LDL, which was operate. But as far as making inferences, you know, we'll be able to determine whether it is reasonable, safe and efficacious to actually bring this group of patients to whatever the presumed LDL level is.
Dr. Hutter: Unhhuh.
Dr. Foody: Beyond that, to infer beyond that...
Dr. Hutter: Can't say much more.
Dr. Foody: ...you really can't say much more. But this is a group of patients that - and based on what Paul has said - even that insight, the fact that people with very normal LDL had high CRP.
Dr. Hutter: We'll broaden our target range in terms of people. So Paul, at the end that's what we're going to be able to say, what you're not going to be able to say. Is that fair? That we don't know how far to push it, we don't know the exact mechanism and other trials will be necessary for that?
Dr. Ridker: Well, I think that the top line result might be: If your CRP is elevated we can prevent a heart attack, stroke and a cardiovascular death. It might also be we can't. That's why we do the trials.
Dr. Hutter: Either answer is important.
Dr. Ridker: Right.
Dr. Hutter: Okay.
Dr. Ridker: The second level would be if positive we certainly will do a number of pre-specified analyses looking at relative reductions in LDL versus relative reductions in CRP, but I actually agree with both Rob and JoAnn. That is not going to nail it down.
Dr. Hutter: Okay.
Dr. Ridker: That's why we're going to try a direct antiinflammatory trial.
Dr. Hutter: That's a superb idea. Direct antiinflammatory versus what? Versus a statin? Or versus nothing?
Dr. Ridker: Well that trial is actually designed in high risk secondary prevention where everyone is already on a full dose of statin. Get that out of the equation.
Dr. Hutter: Gotcha. Okay. So it's going to be an additive study?
Dr. Ridker: That's right.
Dr. Califf: Dolph, I think there is a really important issue here for the patients that you described, and I worry a lot that by naming these targets without doing a proper trial for target. The only way to really know about a target is to say, we're gonna randomize people, to either get pushed to this level or that level based on available therapies, which of course we did in ACCORD, and you've seen the result of that.
Dr. Hutter: Yeah. Yeah.
Dr. Califf: When you take people and you treat them all, and then you see where they ended up, and you try to then draw an inference about where you ought to be, the people who responded differently to the drug may have been different to begin with.
Dr. Hutter: Gotcha.
Dr. Califf: And so if we beat it into people's brains that if it's 71 and your target was 70, you're going to take an additional drug. We may actually be harming them by pushing additional drugs on them.
Dr. Hutter: Good point, good point. I think you make a very valid point that the target is very difficult to assign it, but the concept of who to give the drug to is a very valid thing to test. Well, listen, that's a great discussion and we will all stay tuned because not only about the CRP results with statin, but also the antiinflammatory drugs. Thank you all very much.
Dr. Califf: It was a pleasure.
Dr. Ridker: Thank you.
Dr. Foody: Thank you.
Dr. Hutter: And thank you for joining us. I'm Dolph Hutter.
Dr. Hutter: Hello. I'm Dolph Hutter. Welcome to the American College of Cardiology, Conversations with Experts. In this program we will discus statins and inflammation. With me today is Dr. Paul Ridker from the Brigham and Women's Hospital in Boston.
Dr. Ridker: Pleasure Dolph.
Dr. Hutter: Dr. JoAnne Foody, from the Brigham and Women's and Faulkner Hospital in Boston.
Dr. Foody: Glad to be here.
Dr. Hutter: And Dr. Rob Calif from Duke. Thank you all for joining us. Now first of all let me just throw out some different topics. You know we heard the word pleiotropic effects of statins. We're not going to talk about LDL lowering. That's pretty well summarized. Pleiotropic effect, what does that mean? Paul, what does that word mean?
Dr. Ridker: Well if I probably had my way I'd get rid of the term pleiotropic really. Pleiotropic to me means a drug has many effects throughout the body, but that's true for every drug I prescribe. I think what we're more interested in are their on-target effects - in the case of statins on lowering LDL cholesterol - and are there other effects that might or might not be beneficial for the patient.
Dr. Hutter: Okay.
Dr. Ridker: I prefer that kind of context than Pleiotropic.
Dr. Hutter: What do you think JoAnne? Do you think it's a misnomer?
Dr. Foody: Absolutely. I think that this pleiotropic really has...it's very hard for people to understand. I think we really need to focus on the on-target, as Paul has said, the lipid-lowering, LDL-lowering effects, as well as potential other effects that may be beneficial.
Dr. Hutter: Rob? What's your take?
Dr. Califf: My insight into this is coming from being able to now look at genomic technologies, something Paul has been doing for awhile, but when you look at the effects of a drug on let's say gene expression, there can be hundreds of genes effected. If you look at metabolomic profiles you're finding a lot of activity that occurs at distant pathways, biologically, than we were even thinking about. So I think most of the world now is moving to this concept. On-target means you developed the drug for a reason and you want to measure, Are you affecting that mechanism? And then you're looking throughout the whole universe of other biological pathways where undoubtedly a lot is happening with every drug that we ingest systemically. We don't know the meaning of most of it, but we're beginning to learn about it.
Dr. Hutter: Yeah, that's a very good point. I guess when you go back to aspirin, you know the "pleiotropic" effect was just a different effect than for what it was initially used. So we can get rid of that word do you think? Good. Because it took me a long term just to learn how to spell it, so at least I don't have to remember that anymore.
What about antiinflammatory effects? Are there any...statins have any role in antiinflammatory effects?
Dr. Califf: Well you know I'd say there is definitely an antiinflammatory role if you measure a marker like CRP, which is one of the markers for inflammation, it goes down with statins (Figure 1). The questions are what does it mean? Just defining inflammation, it's a fairly broad term and it means a lot of different things are going on. As a clinical trialist, what I'd say is measure things, they change, it means something is going on. Understanding it takes a lot of empirical research. The clinical meaning of this is complex and we'll sort out by measuring things like what's the mortality rate, and what other clinical phenomena occur when you take a statin or don't take one.
(Enlarge Image)
Figure 1.
Average Change in CRP by Study Characteristics
Dr. Hutter: All right. JoAnne, so you think that statins right now, which is the primary for LDL lowering and not for antiinflammatory action?
Dr. Foody: Well, I think as Rob said, that the real issue is that we see that statins lower markers of inflammation. The question is whether that's due entirely to the LDL lowering effect and thereby causing that as a biomarker? Or if that's something unique with statins. I tend to believe that the majority of that effect is due to the LDL lowering.
Dr. Hutter: Okay.
Dr. Foody: And that we see that parse out that way.
Dr. Hutter: I want to save you for a little bit later, Paul, because I'm gonna ask you specifically about CRP, but Rob...let's go back to this little question. Is most of the beneficial effect defined by the lowering of the LDL? Or is there a fair amount that we can't explain? You said 70% is related to the LDL lowering per se?
Dr. Foody: Well I didn't give a number, but if we look at meta-analyses...
Dr. Hutter: I guess that's something I have read about, you know, but...
Dr. Foody: If we look at meta-analyses you see that the predominant component is related to the reduction in LDL. And that's debatable. I'm sure Paul will have a comment.
Dr. Hutter: What do you think about that, Rob?
Dr. Califf: Yeah, I'd say this is always an impossible question to really answer. But if you draw a regression line through the lowering of LDL and the clinical benefit, there is a nice relationship. But that doesn't tell you for sure that the LDL lowering itself is a direct mediator, it just tells you when it's moving things get better. And it's moving could be an indicator that something else entirely different is going on. So if I had to bet, I'd say it's LDL lowering based on what we know.
We're doing a kind of an interesting study funded by the NIH in teenagers with lupus randomized on statins or placebo. Their LDL's are not very high, but they get atherosclerosis, or something that looks like atherosclerosis. So we'll be having those results actually in just a year or so. That might give us some insight.
Dr. Hutter: And there is also data from the non-statin literature that lowering of the LDL is beneficial. I mean, Paul, I mean there is a lot of data about that in terms of other ways of lowering the LDL, including such things as diet, plasmapheresis, and things like that. There are clinical studies that have indicated that the LDL is a very important target. Would you agree with that?
Dr. Ridker: Absolutely. So if we look at this broadly we know that diet is a terrific way to lower heart disease risk, and yes it lowers LDL. The POSCH trial showed us that ilial bypass lowers LDL and that seems to be good. The tension has been there's other drugs that lower LDL that haven't been so good. Post-menopausal HRT is a classic example of a drug that lowers LDL raises HDL, and didn't do a very good thing. For me it's of interest because it's a drug that happens to raise CRP, so it's an interesting question. Torcetrapib was a problem for us.
Dr. Hutter: Yeah.
Dr. Ridker: Very good LDL-lowering drug, terrific HDL raising drug didn't work so good.
Dr. Hutter: It not only didn't work so good and it caused some harm.
Dr. Ridker: That's right. So the tension here is, as we've been talking about, is it the statin - because that's what the trials tell us - the trials tell us if you're going to take a drug, the statins are extraordinarily good at lowering the risk of heart attack, stroke, cardiovascular death, and it happens to lower LDL. I would probably argue, and it happens to lower CRP, and isn't that interesting. That this drug does two things in my mind that are very effective, but we know that at the end of the day from my practice largely for those patients who can take the drugs, that's my first choice because I know from the trials that's what it does.
Dr. Hutter: All right. Now, let's move on to CRP and then...and I know you've been doing some studies and you've given us some information about CRP. What is the past information about the role of CRP? Let me first ask you, Paul. Is CRP an adequate marker of "inflammation?" I mean, is that as good as anything else? Is it a good surrogate marker? What does it mean? Do you think CRP is a good valid indicator of inflammation?
Dr. Ridker: It's wonderful question, and in some ways, the problem is that when we published our first CRP paper, which is now 1997, I would have hoped that this many years later we'd have a better marker of inflammation. We don't....
Dr. Hutter: Yeah.
Dr. Ridker: That's in some ways perhaps a disappointment. But also it maybe just says that what you're really after is a surrogate marker of this process. That does not mean that lowering CRP per se is a target. That's the tension in this field. It does mean inflammation seems to matter. Most inflammatory markers give you a similar sense of what's going on. The problem in this field has been, yes, if you've got an elevated CRP for probably any reason, risk of a heart attack or stroke is high. That's true in primary prevention; it's true in secondary prevention. In the statin arena, as Rob pointed out, these drugs lower CRP. And we've done some analyses of completed trials like AFCAPS/TEXCAPS which suggested that there was benefit in people who had a lowish LDL and a high CRP, within PROVE IT (PROVE IT-TIMI 22 - Lipid Lowering Results) and A to Z (A to Z - Phase Z), the demonstration was shown that if you not only get the LDL down below an aggressive target, say of 70 mg per deciliter, but also got the CRP down below a target of about 2 mg per liter, the patients seem to do better (Figure 2). And that's a clinical thing though, it's not necessarily...
(Enlarge Image)
Figure 2.
PROVE IT-TIMI 22: Cumulative Incidence of Events Based on LDL or CRP Levels Achieved with Therapy
Dr. Hutter: Well they definitely did better, didn't they? I mean, statistically they did better.
Dr. Ridker: Well they clearly do better. We're not quite sure why they do better.
Dr. Hutter: Gotcha, okay.
Dr. Ridker: And so the tension at the research end is why, the clinical end is, Hey, they did better, why wouldn't you want to be in that low CRP/low LDL group. And so this notion of dual goals has become a relevant question. But all that being said, as Rob correctly would point out, you need a fundamental endpoint trial to test all of this.
Dr. Hutter: Interesting that you should both mention that, and all three of you have mentioned that. Is there an endpoint trial in progress? Would you like to comment on that possibility.
Dr. Ridker: Well, yeah, so with help from the NIH and investigators around the world, in 2003 we launched a very large clinical trial, called JUPITER. JUPITER is pure primary prevention, so it's healthy, middle aged men and women. They don't qualify for a statin. That's the key. They have an LDL cholesterol in primary prevention of less than 130, but they've got a CRP above 2. So they're in this high risk group.
Dr. Hutter: So what is their average lipids? I mean what is the average of the population? Is it like at 115? Or 100? Or 90? Or what?
Dr. Ridker: Well, we randomized nearly 18,000 patients around the world in this trial. The average LDL on the weigh-in is only 104.
Dr. Hutter: Wow.
Dr. Ridker: And the HDL is 51. So these are not folks...
Dr. Hutter: A lot of people wouldn't treat those people.
Dr. Ridker: I must say in my own practice I wouldn't.
Dr. Hutter: Yeah, yeah. But they all have CRPs of over 2?
Dr. Ridker: That's right. The CRPs are over 2. The average is around 3-1/2 to 4, and half are getting rosuvastatin and half are getting placebo, and the question will be was that a good idea or not?
Dr. Hutter: Rosuvastatin in a high dose? Or a moderate dose? Or...?
Dr. Ridker: We actually elected to go with a pretty high dose.
Dr. Hutter: Okay.
Dr. Ridker: 20 mg.
Dr. Hutter: 20 mg.
Dr. Ridker: The idea being let's dramatically lower the LDL, let's dramatically lower the CRP, and see whether that's beneficial or not.
Dr. Hutter: Now how are you going to know? Rob, weigh in on this because you're a well established trialist: How are you going to know which it is? How do you differentiate that if you get the CRP down to 1, got the LDL down to 40, which is the beneficial effect?
Dr. Califf: Well why do you care so much I guess would a question I would ask. I mean...
Dr. Hutter: Well, okay.
Dr. Califf: If I were a patient, and I said okay, you know it's interesting to know what my biochemical measurements are. What I really care about is am I gonna have a stroke, and am I gonna die, or have a heart attack. And if Dr. Ridker can tell me, based on this trial, people like you have a much lower risk of having a heart attack or a stroke, that's the main thing. That's what the rest of us like to argue and discuss.
Dr. Hutter: Well actually not...you know I see a lot of patients come in and say, you know, "My LDL is 69, Doc, or 68 and I feel well. I'm getting little muscle aches, I really don't want to push this dose, do I really have to, Doc?" And somebody will say "Well let's check your CRP? If it's 5, then yes you have to." I think it is a practical question because there are a lot of patients where you don't want to push it or you can't push any harder, and should you really try to push. So, I think it does make a difference whether or not it's the CRP or the LDL.
Dr. Califf: It still doesn't tell you which it is, because the drug's going to lower both, even in the range that Paul is talking about.
Dr. Ridker: So I would say that Rob is correct about this. This trial was designed for public health. This trial was designed to say, are there a lot of people who...
Dr. Hutter: Good point.
Dr. Ridker: ...just don't have high cholesterol and therefore we're not giving these drugs because we're wed to a biomarker who have a high CRP so risk is up. Will they benefit.
Dr. Hutter: Okay.
Dr. Ridker: So the question would be, what if JUPITER is positive and what if JUPITER is negative. If it's positive, I agree with Rob. The problem is a situation where we say in a very practical sense, if your CRP is elevated you probably would be on these drugs if it's cost effective, and the usual kind of things. There is safety information here as well. We're putting, you know, half of these 18,000 people on a dose...
Dr. Hutter: Right. Yeah.
Dr. Ridker: ...that's going to drive the LDL to 40 or 45? We need to see if that's safe. The pathophysiologic question of is it inflammation reduction or is it lipid reduction is actually going to require another trial.
Dr. Hutter: Okay.
Dr. Ridker: And we're actually talking to the NIH about how to do that with target antiinflammatory agent, rather than a statin.
Dr. Hutter: Oh, well that'll be interesting. That will be interesting. So, are you going to be able to say...by the way, this trial is going to be done in another year or so do you think?
Dr. Ridker: JUPITER is an endpoint driven trial which means that it's over when it reaches a certain number of endpoints. When the...
Dr. Hutter: Oh, so you don't know exactly how long it's going to go.
Dr. Ridker: That's right. we're guessing another year, year and a half.
Dr. Hutter: Okay, good. So at the end do you think you'll be able to say...well, you make a good point. This is a epidemiological question. People with this thing ought to go on it. But you won't be able to tell us how far we should push the CRP or the LDL, is that right? The trial isn't designed to do that. Is that what you're both telling me.
Dr. Califf: I've talked to Paul about this. I'd love to hear what JoAnne says about how much you can infer by looking at post treatment values about prospective targeting.
Dr. Hutter: Yeah. Yeah.
Dr. Califf: I'm nervous about it.
Dr. Foody: Well, I agree...
Dr. Hutter: Well, it sounds to me like you can't even answer the question, but let's see what...
Dr. Foody: Well, no, but you can answer the question of what the utility is of defining through CRP in an otherwise low risk population whether there is an advantage of using a statin.
Dr. Hutter: Okay.
Dr. Foody: You certainly can't make inferences around underlying pathophysiology in relation of inflammation, LDL, which was operate. But as far as making inferences, you know, we'll be able to determine whether it is reasonable, safe and efficacious to actually bring this group of patients to whatever the presumed LDL level is.
Dr. Hutter: Unhhuh.
Dr. Foody: Beyond that, to infer beyond that...
Dr. Hutter: Can't say much more.
Dr. Foody: ...you really can't say much more. But this is a group of patients that - and based on what Paul has said - even that insight, the fact that people with very normal LDL had high CRP.
Dr. Hutter: We'll broaden our target range in terms of people. So Paul, at the end that's what we're going to be able to say, what you're not going to be able to say. Is that fair? That we don't know how far to push it, we don't know the exact mechanism and other trials will be necessary for that?
Dr. Ridker: Well, I think that the top line result might be: If your CRP is elevated we can prevent a heart attack, stroke and a cardiovascular death. It might also be we can't. That's why we do the trials.
Dr. Hutter: Either answer is important.
Dr. Ridker: Right.
Dr. Hutter: Okay.
Dr. Ridker: The second level would be if positive we certainly will do a number of pre-specified analyses looking at relative reductions in LDL versus relative reductions in CRP, but I actually agree with both Rob and JoAnn. That is not going to nail it down.
Dr. Hutter: Okay.
Dr. Ridker: That's why we're going to try a direct antiinflammatory trial.
Dr. Hutter: That's a superb idea. Direct antiinflammatory versus what? Versus a statin? Or versus nothing?
Dr. Ridker: Well that trial is actually designed in high risk secondary prevention where everyone is already on a full dose of statin. Get that out of the equation.
Dr. Hutter: Gotcha. Okay. So it's going to be an additive study?
Dr. Ridker: That's right.
Dr. Califf: Dolph, I think there is a really important issue here for the patients that you described, and I worry a lot that by naming these targets without doing a proper trial for target. The only way to really know about a target is to say, we're gonna randomize people, to either get pushed to this level or that level based on available therapies, which of course we did in ACCORD, and you've seen the result of that.
Dr. Hutter: Yeah. Yeah.
Dr. Califf: When you take people and you treat them all, and then you see where they ended up, and you try to then draw an inference about where you ought to be, the people who responded differently to the drug may have been different to begin with.
Dr. Hutter: Gotcha.
Dr. Califf: And so if we beat it into people's brains that if it's 71 and your target was 70, you're going to take an additional drug. We may actually be harming them by pushing additional drugs on them.
Dr. Hutter: Good point, good point. I think you make a very valid point that the target is very difficult to assign it, but the concept of who to give the drug to is a very valid thing to test. Well, listen, that's a great discussion and we will all stay tuned because not only about the CRP results with statin, but also the antiinflammatory drugs. Thank you all very much.
Dr. Califf: It was a pleasure.
Dr. Ridker: Thank you.
Dr. Foody: Thank you.
Dr. Hutter: And thank you for joining us. I'm Dolph Hutter.
