HUTTER, MD: Hello, I'm Dolph Hutter. Welcome to the
me to discuss the topic are Dr. Deepak Bhatt, an interventional cardiologist at
the Cleveland Clinic Foundation; Dr. James Tcheng,
Associate Professor of Medicine at
DOLPH HUTTER, MD: Listen, I think this is going to be an exciting topic. Let's start out now, just to tell the audience what we're going to do, I'm going to ask Jim to first of all define what we're talking about in terms of a non-ST elevation MI, then I'm going to ask Deepak to define how do we stratify patients.
Then I'm going to ask Deepak to tell us how we risk-stratify these patients. And then I'm going to ask Glenn to say, if we do have a PCI option, how do we decide who needs to go to PCI?
So let's start out. What is the definition of what we're talking about?
DOLPH HUTTER, MD: So, Jim, let's start off with a definition of NSTEMI.
JAMES E. TCHENG, MD: Great. NSTEMI is the acronym for non-ST elevation myocardial infarction, which also goes by a perhaps larger term, the acute coronary syndromes. I think the first place to start off with is that this is an enormous problem. If you look at just the number of hospital admissions every year for patients with chest discomfort, I think we realize that this is one of the leading problems in American health care. If you take the million-plus emergency room visits and then divide those patients out into who has an acute coronary syndrome, you're probably talking at least about 20 to 30% of patients who present with the emergency room admission diagnosis of chest discomfort.
And yet, it's clearly not just everybody with chest discomfort.
DOLPH HUTTER, MD: Right.
JAMES E. TCHENG, MD: This is a high-risk group of patients, patients who have a mortality of perhaps 5 to 10% over the first 30 to 60 days. These are patients defined as new onset discomfort, as existing…
DOLPH HUTTER, MD: New onset of, say, chest discomfort consistent with angina, right?
JAMES E. TCHENG, MD: Absolutely.
DOLPH HUTTER, MD: Okay.
JAMES E. TCHENG, MD: New onset. It could also be preexisting known coronary artery disease with a change in your syndrome.
DOLPH HUTTER, MD: A very important point. So previous stable angina, but all of a sudden an exacerbation of it in the absence of precipitating events.
JAMES E. TCHENG, MD: Correct. It can also be an expression that is perhaps misleading, for example, a worsening of heart failure that is actually based on an anatomic basis worsening of coronary artery disease.
The underlying pathophysiology is really the key point here, and that is our understanding that it represents an active lesion, ruptured plaque and ulcerated vessel that has created some thrombus on top of it that then leads to a new or altered presentation of typical coronary artery disease.
DOLPH HUTTER, MD: Okay. So this person come into the EW. We should remind all of us, I guess, don't forget, women often don't present with classical chest pain. They'll have other symptoms, and you have to think of it.
Now, what should we do once they're in the EW? Deepak, how do you evaluate these people, and how do you risk-stratify them?
DEEPAK BHATT, MD: Well, you know, that's really a key question, risk stratification, and something that's been the focus of a lot of research efforts. I think the biggest breakthrough in terms of diagnosis of acute coronary syndromes in general, and NSTEMI in particular, has been the development and widespread adoption of troponin. So if a patient comes in with a chest pain syndrome, and as you rightly just pointed out, it might even be somewhat atypical symptoms, especially in elderly and/or female patients. But a syndrome where it is concerning for coronary ischemia, measurement of troponin should be one of the first things done, along with an ECG.
DOLPH HUTTER, MD: Right.
DEEPAK BHATT, MD: And those two, I think, are the key risk stratification tools as far as objective evidence in terms of determining how high risk an acute coronary syndrome this is. Presumable, just with the history, we've already established that there's enough concern to label it a type of acute coronary syndrome. But the question now…
DOLPH HUTTER, MD: I'm sorry to interrupt, but let me just…when you mentioned the EKG, I think it's very important that everybody understand that an EKG during pain is extremely helpful. It tells you if you do have ST segment changes, how extensive they are, where they are, and if there are no changes during pain, it makes you think, "Well, maybe this is not coronary."
DEEPAK BHATT, MD: Absolutely. And the time to getting that EKG is something that's pretty important, and increasingly something which I think physicians and emergency departments will be graded by. So a rapid ECG, measurement of troponin, perhaps bedside point-of-care testing of troponin. And then there's an immediate sort of risk stratification that's possible, just from those two pieces of data.
Beyond just a troponin and ECG, the TIMI risk score is something that the TIMI group has developed that has been now validated as an independent predictor of risk. And what this consists of, just to go through quickly, are seven independent predictors in patients presenting with acute coronary syndromes: age greater than or equal to 65 years, the presence of three or more classic coronary artery disease risk factors, a known prior coronary stenosis greater than or equal to 50%, aspirin use in the last seven days, two or more anginal events in the past 24 hours, and then, as I'd already mentioned, ST changes or elevated biomarkers.
So those seven different factors are independent predictors, and if a TIMI risk score adds up to about 0 to 2, that's considered lower risk; , moderate risk; and high risk is 5 through 7. Although my…
DOLPH HUTTER, MD: Okay, that's very helpful. Thank you. So we have EKG changes, pretty objective, and very important to get that right away. The fastest troponin screen, you can get it right away. A clinical evaluation, as you just said, with the TIMI risk factors. Anything else?
DEEPAK BHATT, MD: Well, first of all, with the risk, I tend to, in my mind, lump moderate and high-risk together. Most doctors like to think in sort of in a binary fashion. So in my mind, I either make them lower risk or higher risk.
And as far as other factors that are important, even if the initial troponin is negative, it's important to realize that if a clinician's gestalt is that this is the real thing, real chest pain, to still treat it aggressively. And certain factors, such as prior revascularization, congestive heart failure on presentation, patients with diabetes or renal insufficiency, these often are markers that, even if that initial troponin is negative, if the story is good it probably is the real deal.
DOLPH HUTTER, MD: All right. You know, by the way, when I'm dealing with my patients, I always try to remind them what their angina felt like before, before surgery or whatever, so if they come in the emergency ward and say, "Doctor, this is just like I had before my open-heart surgery," if patients can tell us that, that does help the EW personnel.
DEEPAK BHATT, MD: Absolutely. That's a terrific point.
DOLPH HUTTER, MD: Glenn, let's say we got this patient in here, and he's got ST changes, his troponin's up. I mean, classical risk factors. If we had the option to go to PCI versus intensive medical therapy, what would be the better option of those two, if you had both of them available?
GLENN N. LEVINE, MD: Well, I think Deepak has made my job a lot easier by discussing those high-risk factors, and I think most, if not all, cardiologists would agree that at this point in 2004 there's good data that in patients who have the high-risk markers that he discussed, namely, a positive troponin, ST depression or a high TIMI risk score, we have fairly good data from now numerous trials that a strategy of early catheterization and revascularization is superior to medical therapy alone, most prominently in those with positive troponins.
In the TACTICS study by Chris Cannon, there was a 10% absolute, not relative, but absolute difference in adverse events between those who went to the cath lab early and those who were initially managed medically.
DOLPH HUTTER, MD: Yes, but that…
GLENN N. LEVINE, MD: But clearly…
DOLPH HUTTER, MD: I'm sorry. Go ahead.
GLENN N. LEVINE, MD: So clearly, if someone has both positive troponins and ST depression, I don't think there would be much controversy that early cath and revascularization is a well-established superior strategy in that particular patient.
DOLPH HUTTER, MD: Yes, I would agree. And I'm sorry for interrupting, but I think that that is just superb. Do you all agree on this? Deepak and Jim, do you agree with that statement?
DEEPAK BHATT, MD: Oh, absolutely. 100%.
DOLPH HUTTER, MD: Yes.
DEEPAK BHATT, MD: I think at this point in time the data are really overwhelming favoring an early invasive strategy in high-risk patients.
DOLPH HUTTER, MD: And Jim, what do you think?
JAMES E. TCHENG, MD: Yes, I agree.
DOLPH HUTTER, MD: Oh, okay.
JAMES E. TCHENG, MD: There are additional data, for example, the ISAR-COOL study, which demonstrated that a period of pretreatment with, for example, a glycoprotein IIb/III antagonist, although it helps suppress events, really does not supplant or is not bettered by an early invasive strategy. So we have TACTICS. We have ISAR-COOL. Every piece of data we have speaks to early intervention.
DOLPH HUTTER, MD: So pretty strong information that we really should move to the cath lab.
Now, Glenn, I'm going to come back to you, because I'm in your hospital and I've got the cath lab right there. That's wonderful. That's great. Suppose I'm not in your hospital, but I'm in a hospital close by. There's a certain -- How do you make the decision whether or not to move this patient into the cath lab, even if you're going to have to put him in an ambulance?
GLENN N. LEVINE, MD: Well, I think first, as Jimmy pointed out, non-ST elevation is a distinct entity. The decision is a little bit different than ST elevation MI, where we're talking about immediate transfer for primary angioplasty. In our situation of non-ST elevation acute coronary syndrome, there's certainly less data that we need to immediately package this patient and rush him emergently into our cath lab.
In such a patient, I think it would be reasonable to initially treat with the medications that are used in high-risk patients, such as the IIb/III's.
DOLPH HUTTER, MD: Yes, we'll discuss that next. Yes, right.
GLENN N. LEVINE, MD: But in a patient who has positive troponins an ST depression, it would be very reasonable and probably appropriate to transfer this patient to a facility that does do angioplasty.
DOLPH HUTTER, MD: Assuming that, let's say, you can get there within an hour or two hours, or is there a time limit, do you think? Or you're going to start the medical therapy anyhow, but what would you say about that?
GLENN N. LEVINE, MD: Well, I would say, as far as your medical therapies, and I'm sure Jimmy would agree, since there's good data on IIb/IIIa's, both in ACS and in patients going to the cath lab for angioplasty, particularly high-risk patients. It would be very reasonable to start the IIb/IIIa on presentation in the emergency room, regardless of whether it'll be one hour or two hours or three hours before the patient hits the catheterization lab.
DOLPH HUTTER, MD: And then would you call your referral hospital and say, "I've got this guy. I want to send him in."
GLENN N. LEVINE, MD: I would. Again, I don't think that, unless the patient is having active chest pain with dynamic ST depressions in front of your eyes, in which case I would emergently take the person to the lab, I don't think we have data that this person needs to be emergently taken to the lab.
DOLPH HUTTER, MD: Well, that's a good point.
GLENN N. LEVINE, MD: Versus, say, urgently taken to the lab.
DOLPH HUTTER, MD: All right. That's a good point. So if a guy comes in at in the morning and he's got the markers, but you put him on the programs, which we'll discuss subsequently, you say, "Look, let's get him in there. They can take a look at him next morning." Is that reasonable? If he's stable?
GLENN N. LEVINE, MD: I think that's appropriate, and I don't think we have any data at this point that for a non-ST elevation ACS patient who is not having active chest pain, that he needs to be emergently taken to the cath lab.
DOLPH HUTTER, MD: Okay. Now, Jim and Deepak, let me ask you this. We've got this guy. He's at an outside hospital. He's got ST changes, ST depression, positive troponin. He's quieting right down. We're going to put him on all the medicines that we're going to talk about. Let's say he quiets down beautifully. His EKG normalizes. Would you still want to send him to a center and have a cath at some time, or would you do an exercise test? What do you think in that situation? How do you make that decision? Jim, do you want to start?
JAMES E. TCHENG, MD: Yes. I think we have a fair amount of clinical trials data that have at least indirectly addressed this question, and it's remarkable how consistent the information is. If you look at, for example, CURE, which is a trial in clopidogrel; PURSUIT, which is a trial of eptifibatide; ISAR-COOL, which is a trial of tirofiban. All of these trials show that the longer that you wait for diagnostic catheterization and definitive revascularization, the only thing that occurs is continued accrual of event, including mortality events.
So I would argue that in this patient, even if it cooled down, the standards of therapy, in fact, the ACC/AHA guidelines suggest that early catheterization is clearly indicated. It does not necessarily need to be on an emergency basis, as Glenn has mentioned, but this patient does need to have their anatomy defined and the intent for revascularization at least embraced.
DOLPH HUTTER, MD: Okay, very good. So, Deepak, do you agree with this? Okay.
DEEPAK BHATT, MD: Yes, I think Glenn and Jimmy are right on the mark. Really, the bulk of data support an early invasive strategy. Exactly how early, there is some ongoing investigation to see whether even earlier is better. But for right now, I'd say in a stabilized patient within 48 hours or so is an appropriate time frame.
DOLPH HUTTER, MD: Super. And just for my own two cents, I totally agree. If you've got objective evidence, you never know when they're going to heat up again. I would stabilize them. If they're stable, get them into a setting where they can get an angiogram at the appropriate time. And of course, if they're having ongoing point, then I think it does become an emergent situation.
Okay, now..I'm sorry. Go ahead.
JAMES E. TCHENG, MD: This actually reminds me of a quote from Yogi Berra. I hope I get the quote right. But if I remember, it goes something like this. "If you don't know where you are going, chances are you will end up somewhere else." In that inimitable way.
DOLPH HUTTER, MD: That's great. God bless Yogi Berra. That's super.
Okay, now, listen. I'm in the hospital now. I just can't get a patient there to the, well, I'll tell you what. Let me back up. I'm going to say, either one of these settings, I'm going to start medical therapy. Now, who wants to start? What are the basic principles of medical therapy? Jim, do you want to start?
JAMES E. TCHENG, MD: Yes. I think that the work that's been done over the past decade has been quite remarkable in identifying antithrombotic therapies as really the mainstay of early treatment, that although we like to believe that symptomatic treatment, for example, nitrates, morphine, beta-blockers, actually reduce mortality and improve outcomes. It turns out that the antithrombotic environment has really been the best…
DOLPH HUTTER, MD: Is critical.
JAMES E. TCHENG, MD: …provided the best evidence.
DOLPH HUTTER, MD: Okay. Now, antithrombotic. Heparin or low molecular weight heparin? If low molecular weight heparin, which one?
JAMES E. TCHENG, MD: Well, until the recent SYNERGY trial, I would have said low molecular weight heparin clearly has the advantage, and particular enoxaparin over unfractionated heparin. SYNERGY does not say that it doesn't. It just, in all honesty, I believe that SYNERGY clearly demonstrates that you shouldn't cross over, that you should decide what you're trying to treat that patient with, that is, low molecular weight heparin versus an unfractionated heparin, and stick with it.
If you go by the metaanalysis route, it still favors, at least weakly favors, a low molecular weight heparin approach.
DOLPH HUTTER, MD: Okay.
JAMES E. TCHENG, MD: What has to be considered, though, is the referral, early referral to the cath lab and the downstream effects of upstream low molecular weight heparin have.
DOLPH HUTTER, MD: Okay. Glenn and Deepak, heparin? Low molecular weight heparin? Quickly.
GLENN N. LEVINE, MD: I agree with Jimmy that SYNERGY is a little less impressive than previous studies. I think it also is going to depend on the interventionalist who the patient is being referred to. If it's an interventionalist comfortable with using enoxaparin in the lab, then I would lean towards enoxaparin unless the patient is going to the lab within several hours of presentation.
DOLPH HUTTER, MD: Very, very good point. Glenn. Glenn, what do you think?
DEEPAK BHATT, MD: Well, actually, Deepak. I think that, you know, the points Jimmy and Glenn raised about SYNERGY and enoxaparin are all accurate. I think if it's, though, a hospital, especially one where the patient might be sitting around for a day or two, probably still the older data, TIMI-11B, ESSENCE, enoxaparin specifically as a low molecular weight over unfractionated heparin.
DOLPH HUTTER, MD: Okay. So you all make a good point. You know, antithrombotic, important. Work it out locally in terms of what's the best way to go with your situation there.
Now, what about antiplatelet therapy? I assume we would all give these people aspirin. Is that correct?
JAMES E. TCHENG, MD: Yes, I think that's a given situation but would not give the patient aspirin, antiplatelet aspirin.
DOLPH HUTTER, MD: All right. So we're going to give, not talking about 100, about 81(mg). Now we're talking about at least 162, probably 325(mg). What dose do you guys use?
DEEPAK BHATT, MD: Well, I, myself, go with, for the acute setting, 325, chew and swallow.
DOLPH HUTTER, MD: Yes.
DEEPAK BHATT, MD: And I do that even if the patient says they took aspirin. Unless it's clearly documented that they've been given aspirin by medical personnel, I give 325.
DOLPH HUTTER, MD: Do you all agree? 325 or 162?
GLENN N. LEVINE, MD: We typically use 325.
DOLPH HUTTER, MD: Okay.
GLENN N. LEVINE, MD: And in fact, we've empowered our nurses in the emergency room to go ahead and give it without a doctor's order.
DOLPH HUTTER, MD: Now I want to get to clopidogrel, and also IIb/IIIa. What about IIb/IIIa? Everybody should get it if they have those risk factors? Who? Anybody.
JAMES E. TCHENG, MD: I think it's a, this is Jimmy, I think the place to start off with is to return to Deepak's comments about risk stratification. The remarkable thing about the IIb/IIIa trials is that the benefit of the IIb/IIIa's really appear to be most pronounced in patients who have either positive markers, particularly troponin, and/or ECG changes, obviously in the right setting.
DOLPH HUTTER, MD: Right. Now, if they have them, they have those two markers, would everybody say start a IIb/IIIa?
GLENN N. LEVINE, MD: Yes.
DEEPAK BHATT, MD: I think if they have both markers then they're quite appropriate. And you have a good data set to support that.
DOLPH HUTTER, MD: Okay. And that's kind of a unanimous feeling, then, amongst our guests here, and I think pretty well around the community, you ought to start that.
What about clopidogrel? Now, let's say you give 300 mg a load. You know, you go to the cath lab. That's great if you can do PCI, but if you say, "Oh, my heavens, we've got to go to the OR," is that a problem? Should we start clopidogrel in addition to a IIb/IIIa? If so, should we load them before the cath, et cetera? What do you guys think?
JAMES E. TCHENG, MD: Well, Dolph, this is the area where there is the least clarity of all of the antithrombotics.
DOLPH HUTTER, MD: That's why I'm asking you guys.
JAMES E. TCHENG, MD: This is a tough one. I think we have to reflect upon the available clinical trials data, particularly the CURE study. But we also have to keep in mind that in CURE there were substantial delays to cardiac catheterization.
DOLPH HUTTER, MD: Yes.
JAMES E. TCHENG, MD: And even after that, when the patient had surgical anatomy, there were additional substantial delays.
So the question in the American environment, where the whole mantra is to get the patient to the cath lab as quickly as possible, you know, the title of our presentation this morning is "Emergency Angioplasty," I think that there are those who would believe, in fact, in our institution, where clopidogrel is typically not given until the anatomy is defined, mainly because of the 5 to 10% of patients who are going to undergo bypass surgery…
DOLPH HUTTER, MD: Yes.
JAMES E. TCHENG, MD: …perhaps the day after that.
DOLPH HUTTER, MD: We tend to do the same thing at the Mass General Hospital. We kind of hold off on that until we make sure what the anatomy is going to be. What about the other two institutions? What do you do locally?
DEEPAK BHATT, MD: Well, you know, my own feeling is that the CURE data are pretty strong and show a benefit across TIMI risk score.
DOLPH HUTTER, MD: That's true. Yes.
DEEPAK BHATT, MD: Unlike the IIb/IIIa inhibitors, which only shine in higher-risk patients.
DOLPH HUTTER, MD: Right.
DEEPAK BHATT, MD: So, you know, I think perhaps from the patient perspective, in terms of reducing ischemic events, getting that clopidogrel loading dose in the ED is the right way to go.
Having said that, you know, at the Cleveland Clinic we've always been an institution with a rich surgical history, and our surgeons get upset when we pre-treat, when those patients end up showing up on their operating room table.
DOLPH HUTTER, MD: What do you do then?
DEEPAK BHATT, MD: So it's a tough issue.
DOLPH HUTTER, MD: What do you do?
DEEPAK BHATT, MD: Well, you know…
DOLPH HUTTER, MD: Do you give 300, or just bring them right to the cath lab and then decide?
DEEPAK BHATT, MD: In part, it'll depend on timing to the cath lab, so I think it's got to be individualized. I think, much like the enoxaparin question, if the patient is in a health care system where there's going to be perhaps a substantial delay to catheterization and even though all of us on the call here today work at institutions where pretty rapid catheterization and revascularization occurs, that's really not the reality in the United States, and certainly the rest of the world.
DOLPH HUTTER, MD: Good point.
DEEPAK BHATT, MD: Patients end up sitting around in the hospital for quite a while, so I think the value of medical therapy, especially in those situations, where rapid revascularization is not going to occur, I think medical therapy is even more important.
DOLPH HUTTER, MD: Okay, so good point. If you're going to go right to the cath lab, you know, you might hold off. But if it's going to be a delay, you might want to get it started. And who hasn't commented on this?
GLENN N. LEVINE, MD: Yes, this… I would first…
DOLPH HUTTER, MD: Glenn, yes. Do you agree?
GLENN N. LEVINE, MD: Yes, I'd first agree with Deepak. I think it's important to emphasize to people who will be viewing this program that clearly this is the area where there's least agreement among cardiologists, particularly in the academic community. I would just address a couple things.
DOLPH HUTTER, MD: We're going to have to wrap up.
GLENN N. LEVINE, MD: People have already talked about CURE, but you mentioned, would you add Plavix in addition to a IIb/IIIa? And in CURE, the main study where we quote the benefits of Plavix, very few people receive IIb/IIIa's. In fact it was…
DOLPH HUTTER, MD: Very good point. It's a good point.
GLENN N. LEVINE, MD: Are not, not utilized at all. So there really is no randomized data. If you give a IIb/IIIa, it's of clinical benefit to additionally give Plavix.
DOLPH HUTTER, MD: All right. And you handle it pretty much the same way. You make an individual decision, depending on the timing of the cath, et cetera?
GLENN N. LEVINE, MD: Yes, we do. We usually, again, wait until the anatomy is defined.
DOLPH HUTTER, MD: Yes.
GLENN N. LEVINE, MD: And I actually looked at the amount of patients with ACS who go to CABG during their index hospitalization over the last decade. We looked at every randomized trial and every registry, and it turns out it's about 13% of patients.