Treatment of the Post-stent Patient (10/2004) with:DOLPH HUTTER, MD   PETER B.
BERGER, MD  STEVEN R. STEINHUBL, MD

DOLPH HUTTER, MD: Hello, I'm Dolph Hutter. Welcome to the American College 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 Duke University 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 that.

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 antiplatelet therapy.

DOLPH HUTTER, MD: And that was theoretical considerations, is that correct?

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 thereafter.

Stent thromboses still continue to occur in these patients, but they occur at a very stable, very low rate that seems to be relatively constant.

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 two to three 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 greater separation.

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 so far.

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 inhibitor.

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 description?

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 serologic one.

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 the risk.

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 therapy.

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 anatomic reasons.

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 longer-term clopidogrel.

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 data?

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 vasculature.

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 process.

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 basically...

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 reasons...

DOLPH HUTTER, MD: Would you stop the aspirin before the clopidogrel?

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 Dolph Hutter.