Interview with Dr. Paul Ridker, the Lead Investigator of the Jupiter Study

Fuente: AACC -Podcasts

Host: Welcome to the first podcast from Clinical Chemistry. This is
Bob Barrett. The February issue of the journal highlights some
of the latest research from several groups regarding C-reactive
protein. My guest is one of the authors in this month's issue,
Dr. Paul Ridker, the lead investigator of the landmark study,
Jupiter. He is the Eugene Braunwald Professor of Medicine at
Harvard Medical School and the Director of the Center for
Cardiovascular Disease Prevention at the Brigham and
Women's Hospital in Boston.

Dr. Ridker, can you tell our listeners what the Jupiter trial was
all about? Why even consider doing a study of statin therapy
for patients with low levels of cholesterol, but high levels of
high-sensitivity C-reactive protein?

Dr. Paul Ridker: We've known for 40 years that almost half of all heart attacks
and strokes occur among individuals who actually have
average, if not low levels of cholesterol. That doesn't mean
cholesterol's not important; it's terribly important. But we've
got to move beyond simply screening for cholesterol to
understand what high risk is. We've also found that
inflammation, the process by which our bodies fight off
infection and heal itself, is a major determinant of vascular
risk. And so the concept of the Jupiter trial was, let's identify
patients who are at risk of heart attack and stroke not because
they have high cholesterol, but because they have a high level
of a new blood marker for high sensitivity C-reactive protein, or
hsCRP. And let's see if statin therapy can lower vascular event
rates in this group, which is very relevant because we'd shown
many years ago that statins lower C-reactive protein levels in
addition to lowering cholesterol.

Host: You had done a pilot for this trial where you evaluated highsensitivity
CRP and cholesterol previously in the Air Force and
Texas CAP trial. Is that why you didn't study in Jupiter those
with low cholesterol and low CRP?

Dr. Paul Ridker: That's very important. In the AF CAP's/TEX CAP's trial, which
we published back in 2001, we showed that if you had low
cholesterol and low hsCRP, yes, you got an LDL reduction with
statin therapy; but actually, there was no clinical benefit for
the patients at all in terms of preventing heart attack and
stroke. But in contrast, when the LDL cholesterols were low
but the CRP level was high, that group got a very large risk
reduction: fewer heart attacks, fewer strokes, fewer
cardiovascular deaths. But that was a post-hoc analysis, and
so we knew we had to design a major prospective clinical trial
to directly test would statin therapy lower risk in people who
normally would not get statin drugs because their LDL is low
but their CRP is high. But you're correct, that's exactly why we
did not study low cholesterol/low CRP patients. That would be
a 50- or 60,000 patient clinical trial, which would be unlikely
to show any benefit based on prior science.

Host: Okay. So what did the Jupiter trial find?

Dr. Paul Ridker: Well, Jupiter was quite extraordinary. I had the honor of being
the principal investigator of this study, which really organized
worldwide; in 26 countries, we had over 1,000 physician
participants and nearly 18,000 patients. This trial, though,
was stopped nearly 2½ years early by its State of Safety
Monitoring Board because of an overwhelming benefit for
patients. From the primary trial end point, which was first ever
event of heart attack, stroke, revascularization or
cardiovascular death, there was a 44% reduction, which is
almost twice the magnitude we anticipate when we give these
drugs to patients with high cholesterol. For heart attack, it was
a 55% reduction, and for stroke a 50% reduction. For bypass
surgery, it was cut almost in half. And perhaps the most
remarkable finding was that all-cause mortality/total death
was down by 20%. These are really unprecedented findings.
Normally when we give a statin to patients with high
cholesterol, we expect 20-25% benefits. In this trial, we're
seeing rates nearly double that. And I think what that tells us
is that biologically we have really hit the sweet spot here. By
targeting inflammation, we've shown that you can do a
remarkable job lowering vascular risk.
It's also important to recognize that the Jupiter investigators
enrolled almost 7,000 women and almost 5,000 minority
patients. These are groups who really have been understudied
in previous trials, and they got very large reductions. In fact,
every single subgroup in the trial had a statistically significant
benefit, including the individuals who had an elevated hsCRP
and no other risk factor at all. So these are people with no
hypertension, no diabetes, they don't smoke, LDL is low, HDL
is good. Their only risk is an elevated CRP, and event rates are
cut almost in half. So all new guidelines are gonna have to very
seriously consider, does this mean we should be treating and
targeting inflammation as much as hyperlipidemia?

Host: Very impressive study, very impressive. What are the publichealth
implications?

Dr. Paul Ridker: Well, at a public-health level we have to rethink the guidelines
for detecting heart-attack risk and how we go about treating
that risk. Right now there are individuals at the NIH whose job
is to sit down and think through these data, but there are
some straightforward issues at hand. A guy named Robert
Glenn, who is the Study Statistician for Jupiter, has estimated
that if you took the strategy of screening and treatment that we
tested here, you would prevent more than a quarter of a million
heart attacks, strokes, bypass procedures, angioplasties and
cardiovascular deaths in the United States alone over a fiveyear
period, and that's very conservative because it's not even
dealing with patients who have intermediate levels of LDL and
a high hsCRP. That's strictly a calculation of people who have
low LDL. You have to remember, these people started with a
cholesterol level that was -- the LDL was only 108. It dropped
down to an LDL of 55, 25% of this trial has an LDL below 40,
and these are levels that previously were considered
worrisome; but the fact is that we're not seeing any cancer risk,
we're just seeing very large benefits.
So I think we have to recognize two things: first, inflammation
on its own is indeed a major determinant of vascular risk, and
we now have a class of drugs that can safely lower that risk;
and then in general, we have to rethink the whole concept of
what is a low LDL cholesterol. We would probably argue
physiologic levels of LDL are probably 45, 55; that's what we
achieved in this trial. And so these people who had no
indication for a statin because their cholesterol was actually
considered near optimal, well, we now know those are not
near-optimal levels and levels have to come down a great deal
more.

Host: Hmm. Many physicians remain confused about high-sensitivity
C-reactive protein and regular CRP. What can you tell us about
stability of CRP levels over time and why the high-sensitivity
CRP test is needed?

Dr. Paul Ridker: Both are important questions. The hsCRP test is crucial for all
cardiovascular risk prediction. This has been the test used now
for more than a decade in the research community and allows
us to measure the CRP levels with great fidelity in the low
range that's necessary for this process. Perhaps equally
important is the confusion about the units these are reported
in. The so-called regular CRP test is traditionally reported out
in milligrams per deciliter (mg/dL); the hsCRP test which is
needed for this purpose is reported out in milligrams per liter
(m/L). That's a tenfold difference. So a lot of physician and pat
confusion is simply on the basis of ordering the wrong test.
This is something that the Clinical Chemistry community can
help us to sort out. We really don't have to have this confusion,
and from the primary-care physician's perspective and I
suppose the pat's perspective, this is just unfortunate
confusion.

Host: So what's the bottom line here? Should all patients have a
high-sensitivity CRP evaluated at the same time they get
cholesterol checked and, if so, what age should they start?

Dr. Paul Ridker: Well, we have to wait for the guidelines to come out and they
likely will change at some point in the next six to eight months.
I think the research clearly tells us that knowledge of your
hsCRP, along with knowledge of your total and HDL
cholesterol, helps to better predict vascular risk. We publish
something called the Reynolds Risk Scores, which are available
free on the internet that really encompass this idea by
including a marker of inflammation -- that's the hsCRP -- and
a marker for genetics, a yes/no question of family history, and
it greatly changes who is at high risk and who is at low risk
and that tells us we can do a better job.
The question then is when do you do this. I think that the
standard is probably to start around age 40 or age 45, the
same time we would consider therapy for those individuals who
are at elevated risk. The real issue, of course, is if your CRP is
elevated, just as if your cholesterol is elevated, the first step is
not a statin; the first step is diet, exercise, smoking cessation
and getting into a good preventive program. What Jupiter does
say, however, is that beyond lifestyle efforts, it's now very clear
that a pharmacologic approach can result in major benefits.

Host: Would family history change the age you'd start having these
tests?

Dr. Paul Ridker: Yes, it does. If your family history of heart disease is strong,
and what I mean by that is a brother or a father who's had a
heart attack before age 55, a mother or a sister with a heart
attack or strong before age 60, that's what we consider
Audio Transcription by Tech-Synergy Page 5 of 6
premature heart disease. Then I think we would screen
actually in your 20s.

Host: Okay. Well, last, give us a glimpse of where your research in
this field is going. Is there anything beyond statin therapy that
we should know about?

Dr. Paul Ridker: Well, the statins are really quite extraordinary because they're
twofers: they both lower cholesterol and lower inflammation,
and the benefit of these drugs has been proven again and
again. So that's a very straightforward issue.
The Jupiter trial will probably have impact in terms of the
numbers of individuals who go on statin therapy, and again
that's the public-health balance from the cost of this approach
and the benefit we have for preventing disease. But the future
of this field is asking questions about if inflammation, which is
what the hsCRP test detects, is so crucial to vascular biology,
can we actually target inflammation itself as the next wave of
cardiovascular prevention studies. So our group and many
others are now putting together clinical trials that will use
targeted anti-inflammatory drugs and see whether or not these
agents can lower vascular risk; but these are drugs that, unlike
statins, do not also have a beneficial effect on cholesterol or,
unlike aspirin, do not have a beneficial effect on platelet
function and therefore will allow us to directly test this
atherosclerosis hypothesis. That's crucial. One of the important
issues in this field is to recognize that the hsCRP test is very
useful clinically; but we don't yet know if CRP itself is causal --
that's a very controversial arena -- and we don't yet know what
component of inflammation we need to target to lower vascular
risk. It could be the cytokines' driving this process, it could be
the underlying biochemistry here. That's what the future is all
about: how do we target inflammation itself as a way of
lowering cardiovascular risk.

Host: So we've come a long way, but there's still a long way to go.

Dr. Paul Ridker: We've come a long way; but it's remarkable, because the
number of cardiovascular deaths, heart attacks and strokes we
can now prevent is very, very large. The whole understanding,
a real paradigm shift has occurred here that tells us, yes,
cholesterol is important; but this inflammatory process is
equally important, and when you have both the risk is very
high. We now teach the Harvard Medical School students right
at the beginning, atherosclerosis, yes, is a disease of lipid
accumulation; but it's a disease of inflammation
fundamentally, the same way we teach the students
rheumatoid arthritis is a disease of inflammation. That shift in
our thinking is what this is really all about, and I think that
shift is what will drive the research for the future.

Host: Doctor, thanks so much; this has been great.

Dr. Paul Ridker: It's a pleasure.
[END AUDIO FILE: 00:11:43]