Treatment of the Post-stent Patient (10/2004)
with:DOLPH HUTTER, MDPETER B.
BERGER, MDSTEVEN R.
DOLPH HUTTER, MD: Hello, I'm DolphHutter. Welcome to the AmericanCollege of Cardiology, Conversations
with Experts. In this program we will focus on treatment of the
post-stent patient. Joining me to discuss this topic is Dr. Peter Berger,
Professor of Medicine at DukeUniversity and with us via telephone, I would like to welcome Dr. Steven Steinhubl, Associate Professor of Medicine at the University
of Kentucky School of Medicine. Thank you both for joining me.
PETER B. BERGER, MD: Thank you.
STEVEN R. STEINHUBL, MD: My pleasure.
DOLPH HUTTER, MD: Let's start out now. We're going to talk
about the stent patients. But I would like to back up a little bit when we
got bare metal stents a few years ago, Coumadin was tried with aspirin, and
then ticlopidine came along, and it seemed to be even better than Coumadin
but it had side effects, and now clopidogrel. Peter, could you just tell us a
little bit about the history of this progression?
PETER B. BERGER, MD: Sure Dolph.
The initial studies aimed at reducing stent thrombosis and other early
complications after stent placement. Like you said, aspirin and Coumadin was
only marginally affective and associated with a high risk of bleeding.
Five studies showed that aspirin and ticlopidine were better
than aspirin alone or aspirin and Coumadin. But like you alluded to, side
effects with ticlopidine were very frequent, including some life-threatening
ones, thrombotic thrombocytopenic purpura and neutropenia.
Clopidogrel is believed to be every bit as strong as
ticlopidine, but far more well tolerated, better
tolerated, in fact, than aspirin, and it's well tolerated even when large
loading doses are administered, shortening the time to onset of action.
Now aspirin and clopidogrel are preferred over any other regimen
to reduce early complications after stent placement.
DOLPH HUTTER, MD: Okay. That's a very good summary. Thank you
very much. Now Steve, let's go back to the bare metal stents now. What should
we be doing with bare metal stents, or what was the recommendation in terms
of the duration of these drugs after a bare metal stent was put in?
STEVEN R. STEINHUBL, MD: Great question Dolph.
Initially, and just very arbitrarily, the initial duration of ticlopidine on
top of aspirin was four weeks. That was based on some preliminary
re-endothelial data, but no real clinical data and very weak data suggesting
Because of the side effects of ticlopidine and several
registries showing that the vast majority of stent thromboses are occurring
in the first two weeks, most investigators decreased the duration of dual
antiplatelet therapy to two weeks, but this was purely based on the concern
for side effects.
DOLPH HUTTER, MD: Yes, good point.
STEVEN R. STEINHUBL, MD: So clopidogrel became available most
investigators went back to the still very arbitrary four week duration of
DOLPH HUTTER, MD: And that was theoretical considerations, is
STEVEN R. STEINHUBL, MD: Absolutely. Yes.
DOLPH HUTTER, MD: What was the data now? Was there any rebound
phenomena after they stopped the four weeks of clopidogrel? Was there any
data on that?
STEVEN R. STEINHUBL, MD: No. That's a very good question. Both
with looking at two weeks of ticlopidine and four weeks of clopidogrel, when
we've looked at in several of the study registries such as EPISTENT and in
CREDO, and we've never been able to find any kind of rebound or increased risk
Stent thromboses still continue to occur in these patients, but
they occur at a very stable, very low rate that seems to be relatively
DOLPH HUTTER, MD: Okay. Now Peter, let's go on to the
drug-eluting stents now. That's been a whole new addition to our
armamentarium, a lower in-stent stenosis rate, etc., lower clinical event
rate. What's the duration of clopidogrel in these patients?
PETER B. BERGER, MD: Well, the studies examining clopidogrel
in both the sirolimus-eluting stent, Cypher stent and a paclitaxel-eluting
stent, Taxus required or six months in all
of the studies. We don't know what would happen if clopidogrel was stopped
before that. But because paclitaxel certainly delays endothelialization and
sirolimus may possibly, it is recommended as was used in the pivotal trials,
that Cypher stents receive probably three months of clopidogrel and
paclitaxel-eluting stents six months of clopidogrel. But again, this is to
prevent stent thrombosis.
What Steve and others have looked at is the benefits of
long-term clopidogrel not only to prevent stent thrombosis and complications
at the treatment site, but to prevent complications anywhere in the coronary
and extra-coronary vascular bed.
DOLPH HUTTER, MD: Or they call it the segment site or the site
beyond the stent.
PETER B. BERGER, MD: Yes. And when people talk about
long-term clopidogrel going out to one year or even beyond, we're really
talking about anywhere in the vasculature, not just the treated artery.
DOLPH HUTTER, MD: Okay. Steve, what's your take on this? DO you
think that we should be using clopidogrel indefinitely after drug-eluting
stents? What is your feeling?
STEVEN R. STEINHUBL, MD: I think it will eventually be proven
that we should. The data right now will support out to one year, both in CURE
and in CREDO. In both of those studies with the longer duration of treatment,
we see a separation of the event rates between the placebo arm and the
treatment arm, suggesting that with even longer-term therapy we would see a
The ongoing CHARISMA trial, which is looking at high-risk
primary prevention, as well as secondary prevention population in 15,200
patients, that will answer that question. They're expecting followup in that to be out to three-and-a-half years.
Again, this is looking at clopidogrel and aspirin versus aspirin, and we
expect, though we're not sure obviously, that the curves will see greater
separation even with longer duration of treatment.
DOLPH HUTTER, MD: So you're both saying that if you have a
drug-eluting stent - you're talking about a year of aspirin and clopidogrel
PETER B. BERGER, MD: Right. A minimum of a year in high and
intermediate risk patients. I have to be frank that very,
very low risk patients, who admittedly comprise a minority of patients
I see, I don't give long-term clopidogrel. Such patients are on aspirin, a
statin. They are on the clopidogrel for three to six months for their
drug-eluting stent. They are often on a beta-blocker and sometimes an ACE
If I can identify accurately a low risk patient, I often won't
give them that seventh medicine, clopidogrel, indefinitely.
DOLPH HUTTER, MD: Okay.
PETER B. BERGER, MD: Intermediate and certainly high risk
patients, I do treat them at least for a year. And frankly, even though CREDO
and CURE stopped clopidogrel at one year, if my patient who is intermediate
or high risk is tolerating at one year, I go beyond the existing data and
continue it indefinitely.
DOLPH HUTTER, MD: How do you define risk?
PETER B. BERGER, MD: Oh.
DOLPH HUTTER, MD: What's a low risk? It's an anatomical
PETER B. BERGER, MD: That's a really key question.
DOLPH HUTTER, MD: That's why I asked it.
PETER B. BERGER, MD: It's both a clinical, anatomic and
DOLPH HUTTER, MD: Can you summarize it?
PETER B. BERGER, MD: So, for example, a diabetic patient is
at high risk. Suppose someone has had multiple prior thrombotic events while
on aspirin. I consider that to be high risk.
DOLPH HUTTER, MD: Okay.
PETER B. BERGER, MD: If they continue to smoke or have
refractory hyperlipidemia, or suppose, for example, I fix their several 90%
severe lesions, and they are left with 20%, 30% and 40% lesions throughout
their coronary vasculature? Steve has some incredibly exciting data about
some laboratory data that can be used to identify high risk.
DOLPH HUTTER, MD: Okay. Steve, before I come to you about that,
you talked about plaque burden. If there is a lot of diffuse disease around,
that's a high-risk person?
PETER B. BERGER, MD: I think that absolutely contributes to
DOLPH HUTTER, MD: Okay. Steve, what other factors do you use to
define risk in these patients?
STEVEN R. STEINHUBL, MD: I think I agree with Peter's comments, and what we do clinically and what we do today
is you want to identify the patient who has a more progressive or more
aggressive atherosclerotic process and requires that better preventative
There is obviously a lot of good data on the long-term risk of
elevated inflammatory markers, in particularly C-reactive protein.
DOLPH HUTTER, MD: Okay.
STEVEN R. STEINHUBL, MD: So one of the CREDO substudies or one
of the markers we looked at in the CREDO substudy
is baseline CRP levels and the benefit of long-term clopidogrel therapy in
those groups. What we found was that in the placebo arm, that with increasing
tertile of CRP, you had a significant increase in the risk of death, MI and
stroke at one year such that you had two-and-a-half times the risk in the
highest tertile compared to the lowest tertile.
DOLPH HUTTER, MD: And was the benefit of clopidogrel greater in
that group of patients?
STEVEN R. STEINHUBL, MD: Absolutely. That's what was most
exciting, that in the patients with the lowest tertile of CRP, there was no
difference between the control arm and the clopidogrel arm. In the highest
tertile though, randomization to clopidogrel was associated with a 6.5%
absolute risk reduction and nearly 50% relative risk reduction in the
incidence of death, MI and stroke in that group, with the vast majority of
that absolute benefit occurring late with the long-term therapy.
DOLPH HUTTER, MD: That's a very good point. Do you think that
we should get CRP then as we risk stratify these people?
STEVEN R. STEINHUBL, MD: Well, it has made me in patients who
I'm on the borderline of deciding clinically whether to give it, but I think
that these data as a retrospective look at just baseline samples, I think
they need to be confirmed in a larger trial.
But to me what's exciting is that these are very consistent with
what Paul Ridker saw in one of his first studies...
DOLPH HUTTER, MD: With the aspirin.
STEVEN R. STEINHUBL, MD: ...in the Physician's Health Study -
right. That aspirin is really uneffective in those patients with the higher
inflammatory markers, and the fact that clopidogrel is mostly effective, or
really only effective in those with the high inflammatory levels, I think, is
exciting data that we're looking forward to exploring more.
DOLPH HUTTER, MD: You know, in fact, there is data in the
statin use too. Jeff Anderson, looking at a group who had high CRPs or low
CRPs with angiograms, I think with or without PCIs, that the high CRPs were
the ones that benefit from statin therapy. The great effect there was the low
CRPs, the benefit wasn't so impressive. So that's a very good point. As both
you and Peter said, if it's obvious that you're going to need long-term
because of anatomy or diabetes or other things, fine, that's easy. You don't
need a CRP. But if you are in the gray zone, the CRP may tilt you in one way
or the other. Peter, would you agree with that?
PETER B. BERGER, MD: Exactly as you put it. It's not that
long-term clopidogrel is not at all beneficial in low risk patients. It
probably is. But because of economic considerations and the low, absolute
reduction of events, I do try preferentially to identify intermediate and
high-risk patients for the long-term therapy.
DOLPH HUTTER, MD: That's a very valid point. I mean, why use an
expensive drug indefinitely if we don't need to. We should have some better
markers and be selective.
By the way, I guess I should just say for our audience, I mean,
we would all say these people have to be on a statin. Statins, as you know,
have been shown to lower CRP early and quite effectively. So some people are
actually recommending following CRP in terms of your statin dosage, etc.
I'm not aware that clopidogrel lowers CRP per say. Are you?
PETER B. BERGER, MD: Steve, why don't you take it?
DOLPH HUTTER, MD: Go ahead Steve.
STEVEN R. STEINHUBL, MD: You put it correctly Dolph. It has been shown - there have been some very
interesting studies that have shown that it decreases the expected risk in
CRP after percutaneous intervention. But there is no study that I'm aware of
that has actually shown in a stable patient with elevated CRP that by adding
clopidogrel to that regimen, that you definitely decrease CRP. But it's never
been looked at.
Even with aspirin, there is kind of mixed
studies or results...
DOLPH HUTTER, MD: Yes.
STEVEN R. STEINHUBL, MD: ...on whether that specifically lowers
CRP. So we still have to look and determine if that's the case. There are
several studies that do show that it decreases platelet activation obviously,
but decreases the inflammation associated with that platelet activation.
DOLPH HUTTER, MD: Right. That makes sense. If it decreases a
complication during the procedure, you're going to have less of an
inflammatory reaction to the procedure. So that makes good sense.
STEVEN R. STEINHUBL, MD: Yes.
DOLPH HUTTER, MD: Okay, that's pretty straightforward, I think.
What about the other patients now? They don't have drug-eluting stents. They
have either a bare metal stent - and you talked about the risk factors. Are
there other patient groups where you would argue for long-term therapy with
clopidogrel plus aspirin? Peter, would you start?
PETER B. BERGER, MD: Well, until recently there were scant
data about the benefits of clopidogrel among patients undergoing balloon
angioplasty. As you know Dolph, probably only about
5% of patients receive balloon angioplasty in place of a stent, usually for
But a subgroup analysis from the PCI/CURE study did indicate
that even among balloon angioplasty patients, clopidogrel is beneficial. Again,
I think what it gets to is not only the goal of reducing events at the
treatment site, but reducing events anywhere in the vascular bed. Frankly, if
I have the rare patient who gets balloon angioplasty but who falls into
intermediate and high risk subgroups, even that patient I'm administering
DOLPH HUTTER, MD: Good. What about the patient that you're not
going to do any intervention? Their anatomy is not suitable for it; they've
got extensive three-vessel disease; they are diabetic. Should we add
clopidogrel to these patients? Steve, do you want to start? I have been
picking on Peter. Why don't you take that one?
STEVEN R. STEINHUBL, MD: I think it's a very valid question. I
would say that we have - the best data for that comes from the CURE study
where remember the vast majority of patients were treated medically after
presenting with a high risk ACS. That long-term benefit we see in those
patients - so let's say after 30 days where you still see that 20% relative
risk reduction between day 30 and one year suggests to me that in those
groups - medical treatment, interventional treatment, revascularization it
doesn't matter. As Peter has highlighted, you're preventing events beyond
either what that culprit vessel was that brought the patient in for an ACS or
that lesion that we stented in the cath lab, but rather we're treating the
rest of the vasculature and that we do get the same benefit in medically
treated patients as we do in the intervened-on patients.
DOLPH HUTTER, MD: Okay. So you're both making an argument that
a high-risk patient is a high-risk patient and adding clopidogrel to the
long-term makes pretty good sense. Well Peter, again, what about surgical
patients? Are there certain obviously anatomical situations after bypass
surgery where the distal vessels are not very good, the run-off is not very
good? What do you think the role of clopidogrel is there, and is there any
PETER B. BERGER, MD: It's funny that you mention that. The
only data that I'm aware of are from the CAPRIE trial, in which aspirin was
compared with clopidogrel. The clopidogrel group did not get aspirin. In
those patients who had had a remote bypass, clopidogrel dramatically
outperformed aspirin. However, what I think you're referring to is the trend
that I have seen around the country in the absence of data in which surgeons
are more and more frequently placing patients on clopidogrel very early
postoperatively as soon as the chest tubes stop draining blood for the hope
of maintaining graph patency and again, reducing events elsewhere in the
It's an unproven practice. It's becoming more and more common.
My hope is that it is appropriately studied, and we can identify if, indeed,
it's as beneficial as a growing number of surgeons believe it to be.
DOLPH HUTTER, MD: I think you better study it soon because
people are going to not want to use clopidogrel, I think, in some of these
patients. Steve, could you just summarize for our audience what's the
difference between aspirin and clopidogrel in terms of its action, and what
does clopidogrel add to aspirin mechanistically?
STEVEN R. STEINHUBL, MD: Both agents will inhibit a platelet for
the life of a platelet. Aspirin irreversibly inhibits cyclooxygenase enzyme
in the platelet, therefore preventing the synthesis of thromboxane, which is
one of the responses to platelet activation.
The thienopyridines, clopidogrel in this case, will covalently
bond to one of two primary ADP receptors on the platelet, the P2Y12 receptor
and it forms a disulfide bond and stays there for the life of that platelet.
What that does is when a platelet is activated it releases ADP from the dense
granules, which will feed back on surrounding platelets and on the platelet
itself and lead to greater activation.
These are the two pathways that we believe are most important in
amplifying a platelet aggregatory response or a platelet activation response,
so in a local injury and platelets release thromboxane and ADP. So when you
block one pathway, you still have the other pathway that it can help
activation. When you block both though, you would suspect, and we've seen in
clinical studies that you get a very synergistic effect of the combination.
So you're blocking these two primary pathways of the platelet amplification
DOLPH HUTTER, MD: Great. That was a great discussion. I mean,
even I understood that, so you did a job there.
What about side effects, before we wind up? Are there any side
effects to clopidogrel? Peter?
PETER B. BERGER, MD: You know, in the roughly 19,000 patient
CAPRIE trial in which aspirin was compared to clopidogrel, amongst patients
believed to be tolerant to aspirin, clopidogrel actually tended to have less side effects than aspirin. The thing that is clear is
that it does cause a rash twice as frequently.
DOLPH HUTTER, MD: Okay, rash.
PETER B. BERGER, MD: And it will increase bleeding, to a
lesser extent than aspirin, but when you combine aspirin and clopidogrel,
there is more bleeding than aspirin alone. So
DOLPH HUTTER, MD: How about GI distress? Does that occur?
PETER B. BERGER, MD: Significantly than aspirin - half as
frequently as aspirin.
DOLPH HUTTER, MD: But it does occur. I mean, I've seen it, but
much less than aspirin.
PETER B. BERGER, MD: It occurs, and so infrequently that I
often look to see if there is something else that can be causing the GI
distress. And if your patient suffers GI distress on aspirin and clopidogrel,
it's more likely to be from aspirin. And that, by the way, is one of the
DOLPH HUTTER, MD: Would you stop the aspirin before the
PETER B. BERGER, MD: Either stop, or I make sure when I
administer dual antiplatelet therapy that they are getting the lowest dose of
aspirin. Do you know, for years there has been a raging debate about the most
appropriate dose of aspirin? But in recent years, particularly when combined
with clopidogrel, the data are stronger than ever that the lowest dose of
aspirin is most appropriate.
DOLPH HUTTER, MD: Hmm. Well, that's interesting. I might say if
I have some true epigastric distress, I would just
as soon have those patients endoscoped because if
they have a curable lesion, say with an ulcer and things like this, then I
can go back to full doses of everything. So I would encourage us to lower our
threshold to really look into the mechanism of GI distress.
PETER B. BERGER, MD: Perfect.
DOLPH HUTTER, MD: Well listen guys, that was a great
discussion, and it really brings us up-to-date where we stand. Not only are
these two agents, but the duration of using these two agents in people after
coronary stents, both bare metal and drug-eluting, and also other patients.
Thank you both very much and thank you for joining us. I'm DolphHutter.