Update on UA/NSTEMI Management

ADOLPH M. HUTTER, JR., MD: Hello. I'm Dolph Hutter. Welcome to the American College of Cardiology Conversations with Experts. In this program, we will discuss the non-ST elevation MI and unstable angina guidelines from 2002 and the latest trial data surrounding the management of patients with this syndrome.

Joining me to discuss this data is Dr. Dean Kereiakes, Medical Director at the Heart Center of Greater Cincinnati and the Lindner Center at the Christ Hospital in Cincinnati, Ohio; and Dr. Chris Granger, Associate Professor of Medicine at Duke University Medical Center. Thank you both for joining us. This is a timely changing topic. Dean, let's go back to the 2002 guidelines. Tell us, what did they say about this syndrome? Now, remember, everybody, this is not ST elevation MI, this is non-ST elevation MI.

DEAN J. KEREIAKES, MD: You're absolutely right, Dolph, and I think those guidelines, to summarize them succinctly, would place a focus on risk stratification, which was new in the unstable angina guidelines, as they referred to, and also a focus on therapy with antiplatelet agents, specifically aspirin, but also clopidogrel, which could be administered prior to, but we often administration after diagnostic angiography and definition of coronary anatomy. Heparin, or low molecular weight heparin, as the antithrombin agent, was a class 1 recommendation. A IIa recommendation was given to enoxaparin at that time. IIb/IIIa blockade was introduced in the 2002 revision of the guidelines, and can be given either upstream, based on risk stratification, or in the cath lab at the time of PCI.

ADOLPH M. HUTTER, JR., MD: So medical therapy is aspirin, either heparin or enoxaparin, IIb/IIIa.


ADOLPH M. HUTTER, JR., MD: Up front or in the cath lab.

DEAN J. KEREIAKES, MD: And cath within 48 hours if high-risk predictors are present.

ADOLPH M. HUTTER, JR., MD: And how do you tell high risk?

DEAN J. KEREIAKES, MD: You know, I think the best markers for risk the best predictors are clinically evident, such as ST segment shift, recurrent ischemia, left ventricular dysfunction, troponin or positive biomarkers for CK-MB or troponin were the two that are listed.

ADOLPH M. HUTTER, JR., MD: So things that we can get right away in the emergency ward?

DEAN J. KEREIAKES, MD: Pretty much.

ADOLPH M. HUTTER, JR., MD: Markers? You don't get that right away. ST segment changes, obviously. Recurrent angina is clinical observation. Heart failure is a clinical decision.

DEAN J. KEREIAKES, MD: Absolutely, and I thinků

ADOLPH M. HUTTER, JR., MD: And in those, if they have those high-risk, what's the recommendation about cath versus medical therapy?

DEAN J. KEREIAKES, MD: Well, you know, we've adhered to, and I think the weight of evidence would support early invasive therapy in those cases.

ADOLPH M. HUTTER, JR., MD: Was that part of the recommendations in 2002?



DEAN J. KEREIAKES, MD: In the revised guidelines.

ADOLPH M. HUTTER, JR., MD: Pretty clearcut, then. Now, Chris, let me ask you, since then there have been some registries, the CRUSADE registry and GRACE registry, looking at the syndrome. What do those studies tell us?

CHRISTOPHER GRANGER, MD: Dolph, I think they've been really important. And I think they will be incorporated more into future guidelines, some of these observations. And they tell us a couple of key things. They've been able to help us refine risk stratification as a key issue, including real-world populations, because in the clinical trials that some of the previous schemes were devised, the highest-risk patients weren't even included.

They've highlighted the fact that even though we have all this evidence about which the most effective treatments are, we're falling considerably short of applying that effectively, especially in the high-risk patients. The highest risk patients are the ones least likely to get the most proven treatments.

ADOLPH M. HUTTER, JR., MD: Why is that?

CHRISTOPHER GRANGER, MD: Well, I think there probably are two reasons. One is, some of those high-risk patients have legitimate contraindications to some of these effective treatments, and sometimes those aren't always even documented in the chart to fully understand that.

ADOLPH M. HUTTER, JR., MD: Good point. Good point.

CHRISTOPHER GRANGER, MD: But I also do believe that we tend to be risk-averse as physicians, and we need to be following the evidence that the high-risk patients get really important benefits from things like early invasive strategy, which is more effective, probably, in older patients than in younger patients with respect to reducing mortality. And yet, younger patients tend to be cathed much more frequently.

ADOLPH M. HUTTER, JR., MD: Well, good point. Did you find that the older patients particularly were people a little more afraid of using some of these agents?

CHRISTOPHER GRANGER, MD: It was. It's a consistent finding that the elderly tend to be less treated with the proven treatments.

ADOLPH M. HUTTER, JR., MD: Well, Dean, I would think if you were afraid of giving some of these IIb/IIIa's, that's the person you would want to take to the cath lab.

DEAN J. KEREIAKES, MD: Right. Well, your point, Chris, that we learned, it's called a treatment risk paradox, is really disturbing, actually. Because, for example, in a post hoc analysis of TIMI-3b in the first two studies, age over 65 was a powerful predictor of benefit from an invasive strategy.

ADOLPH M. HUTTER, JR., MD: Yet they're less likely to get it.

DEAN J. KEREIAKES, MD: Correct. In TACTICS, it was 75, was a predictor, you know, of benefit from an invasive strategy. But yet, we withhold these therapies. And a couple years back, Matt Roe had a great example from CRUSADE, where the presence of a positive troponin and the level of troponin was correlated with in-hospital mortality. But it didn't correlate with the class I recommendation for cath within 48 hours.

ADOLPH M. HUTTER, JR., MD: So maybe we need to do some education, and maybe shows like this will help.



CHRISTOPHER GRANGER, MD: And there's a flip side, and this has only more recently been recognized, that sometimes these effective treatments are applied, but they're not applied carefully. And there was a nice manuscript in JAMA by Karen Alexander from the CRUSADE registry showing that 40% of the time, patients with acute coronary syndromes are being overdosed with antithrombotic therapy, either enoxaparin, unfractionated heparin or IIb/IIIa inhibitors, and that the overdosing was strongly related to greater risk of bleeding and death.

ADOLPH M. HUTTER, JR., MD: Excellent point. Use the drugs, but use them right. Now, I'm going to come back to, you know, what we should be doing now, but any data since 2002, good data saying that we might, that might influence us, whether or not we should change these guidelines?

CHRISTOPHER GRANGER, MD: There have been a number of very important trials. There have been trials that have reinforced the role of early aggressive interventional strategies. There have been several trials looking at antithrombotic therapy approaches. The SYNERGY trial looked at the issue of enoxaparin versus unfractionated heparin in a population that was going to the cath lab early.

ADOLPH M. HUTTER, JR., MD: Enoxaparin, just to remind us all, is the low molecular weight heparin.

CHRISTOPHER GRANGER, MD: The low molecular weight heparin, enoxaparin, yes. And in fact, there, there was really no major difference between one or the other. Enoxaparin may have been a little bit better at reducing thrombotic complications, but had a little bit more bleeding, and there were a number of complexities. But I think the bottom line there is either unfractionated heparin or enoxaparin in the setting of going to the cath lab is reasonable.

ADOLPH M. HUTTER, JR., MD: But as I recall, one or the other, but don't switch. Isn't that right?

CHRISTOPHER GRANGER, MD: You're exactly right. Don't switch. That's one of the key messages.


DEAN J. KEREIAKES, MD: I think our level of sophistication for assessing renal function and for adjusting the dose of these medications, you know, had you to do the SYNERGY trial over again, Chris, you might adjust the dosing of enoxaparin. Would you?

CHRISTOPHER GRANGER, MD: I think that's a good point.

ADOLPH M. HUTTER, JR., MD: Explain, why is the renal function important with enoxaparin?

CHRISTOPHER GRANGER, MD: Yes, yes. Dosing is very important, and renal function is a key driver for a couple of these treatments, including enoxaparin, which is largely renally metabolized. So a patient who has an estimated creatinine clearance of less than about 30 to 40, we should be reducing the dose of enoxaparin to either 1 mg/kg once a day or some reduced dose.

DEAN J. KEREIAKES, MD: But many of these patients, like a little old lady with a creatinine of 104 could have a GFR, true GFR that's below where you'd expect it.

ADOLPH M. HUTTER, JR., MD: Yes, that's right. Older people have less renal mass, and smaller people, very good point.

CHRISTOPHER GRANGER, MD: And another thing, if I could just also point this out, because this is really under-appreciated. For people who have an estimated GFR of less than 50, the dose of eptifibatide needs to be cut in half. And that was in the CRUSADE registry, that was a major issue. That was not done frequently, especially in the elderly.

ADOLPH M. HUTTER, JR., MD: Now, what about the IIb/IIIa? Any new information about up-front versus in the lab, who should get it, et cetera?

CHRISTOPHER GRANGER, MD: In fact, there is very recent information from the ACUITY trial. I think it's going to take us some time to really understand how that should be integrated into the guidelines, but I think there's an open question about what the value of up front IIb/IIIa inhibitors, especially, as in the U.S., we're going faster and faster to the lab, at least in interventional centers.

ADOLPH M. HUTTER, JR., MD: So so far both look to be equally efficacious?

DEAN J. KEREIAKES, MD: Well, not so much cooling-off time, as opposed to, for example, if you look at prehospital, pre-procedural length of hospital stay, before they have PCI, it's getting shorter and shorter. Wouldn't you agree?


DEAN J. KEREIAKES, MD: The EVEREST trial did show improvement in angiographic parameters, Chris, for example.

ADOLPH M. HUTTER, JR., MD: With up-frontů

DEAN J. KEREIAKES, MD: They gave up-front, upstream tirofiban randomly versus in-lab high-dose tirofiban or abciximab. Those were the three. And in fact, getting upstream tirofiban was associated with better TIMI flow rates, better TIMI myocardial blush grades. These are angiographic parameters.

ADOLPH M. HUTTER, JR., MD: Yes, but no difference in clinical outcome.

DEAN J. KEREIAKES, MD: Correct. The trial wasn't powered to show that.

ADOLPH M. HUTTER, JR., MD: Okay, let me just ask you now, if you guys were going to, you have full carte blanche, and you're going to rewrite the guidelines now and I know this is just asking you to go out on a limb a little bit. Would you change anything in the guidelines?

CHRISTOPHER GRANGER, MD: Yes. You know, and again, with respect to antithrombotic therapy, there are two other trials. There's the OASIS 5 trial, it was a big trial, 20,000 patients. It looked at fondaparinux, the indirect factor 10A inhibitor. And it looked equally effective to enoxaparin, but had half the rates of bleeding. Another issue in acute coronary syndromes is the recognition that bleeding is something that's bad. It's associated with bad outcomes. We probably should be thinking more about strategies to reduce bleeding. Likewise, bivalirudin, in the ACUITY trial, had equal efficacy to enoxaparin, but reduced rates of bleeding in patients who were going quickly to the cath lab. So I think the role of bivalirudin and of fondaparinux will need to be defined in the updated guidelines.

ADOLPH M. HUTTER, JR., MD: Fondaparinux being the anti-10A drug. Yes. Do you agree with that, Dean?

DEAN J. KEREIAKES, MD: I would ask Chris, or both of you, about dosing of clopidogrel, because I'd like to see it opened up to at least 300, up to 600, although there's some controversy whether there really is evidence-based, randomized, controlled trial support for that higher dose.

ADOLPH M. HUTTER, JR., MD: Well, that's a very good point, Dean, and indeed, 300 load, and there are a lot of arguments about 600 load. A lot of people are pushing it. A big pushback initially was the surgeons. They say, "Oh, gee, you give 600. You find a main left (coronary). They've got to go to the OR." More and more, the surgeons are comfortable taking these patients to the OR now. So that's becoming less of an issue. What about 600 versus 300?

CHRISTOPHER GRANGER, MD: I mean, I think we need more data to answer the question. I think it's reasonable to say that we have good platelet function data, that 600 will result in a more potent early effect, which therefore, I think, makes sense to be using...

ADOLPH M. HUTTER, JR., MD: And it's more predictable, therefore...

CHRISTOPHER GRANGER, MD: And it's more predictable.

DEAN J. KEREIAKES, MD: Would you give it before the angiogram or after the angiogram?

CHRISTOPHER GRANGER, MD: Well, I think most centers in the U.S., most tertiary care centers, are holding off until the angiogram, because we do angiography fairly soon after presentation, and then one is, you know, for those patients that need to go to bypass surgery, less of an issue.

ADOLPH M. HUTTER, JR., MD: And I can tell you, that's controversial, also, because there is a push. Some people say you've got to get it up front. You know, we'll worry about the surgical problems later on. You're just going to get a better result. So that's still an arguable point, isn't it? So the guidelines are pretty good. You would put this IIb/IIIa issue much more in the forefront now. Let me just say, I have a case come in midnight. Dean, you're on call that night. I'm the noncombatant. I'm the clinical guy in the EW, but I don't have to get you up out of, or I have to get you up, but I don't have to get up. I'm already up. A patient comes with non-ST elevation MI. He's got ST changes. He's got a kiosk troponin that's positive. Should he come right into the cath? Should you come in and do him right away, or could he wait until 6 or 7 in the morning?

DEAN J. KEREIAKES, MD: Yes, I think that's a great question.

ADOLPH M. HUTTER, JR., MD: That's why I asked you.

DEAN J. KEREIAKES, MD: The number one, yes. And we do this all the time. We do all in-house patients, for example, on Saturday. We've been doing this for a decade, so that our pre-procedural length of stay for this syndrome prior to PCI in patients with unstable angina or non-STEMI is less than eight hours, and has been.

ADOLPH M. HUTTER, JR., MD: But I think around the country the time's getting shorter.

DEAN J. KEREIAKES, MD: It's dropping. I don't come in unless that patient has hemodynamic instability or recurrent ischemia clinically. And that can include refractory arrhythmias, if they're having high-grade ventricular arrhythmias. They have recurrent chest pain symptomatology or evidence of left ventricular decompensation. If they are sound asleep, pain-free and they have a positive marker, we're more likely to start them on an upstream IIb/IIIa blocker, for example.

ADOLPH M. HUTTER, JR., MD: So if you're not going to come in, you're going to put them on a IIb/IIIa just to make sure they stay stable?

DEAN J. KEREIAKES, MD: Yes, and we do them the next morning.

ADOLPH M. HUTTER, JR., MD: Suppose a patient comes in, he's got ST depression all across his anterior V cords. They go back up, but a lot of ST burden. Would that influence you?

DEAN J. KEREIAKES, MD: It's no question it's correlated with mortality, and it also predicts the benefit of an invasive strategy. We call it the ST segment burden across it. The number of leaks and the magnitude of total, and I think that's true.

ADOLPH M. HUTTER, JR., MD: That would bring you in?

DEAN J. KEREIAKES, MD: That would, if it were global and a patient had really a scary-looking EKG with multiple leads.

CHRISTOPHER GRANGER, MD: That patient may be one who's more likely to have multivessel disease or left vein disease.

DEAN J. KEREIAKES, MD: I think so.

CHRISTOPHER GRANGER, MD: But still, having that defined...

ADOLPH M. HUTTER, JR., MD: You've got to find out right away. You can't wait, because they may go down the tube while you're waiting. So again, you're pointing out clinical evaluation and individualization of therapy. Do you agree with that? Do you think that's...


ADOLPH M. HUTTER, JR., MD: Okay, yes.

CHRISTOPHER GRANGER, MD: Although, I have to say, the best timing to do early invasive strategy is not really definitive. But I think it's reasonable to go the next opportunity, the next business day.

ADOLPH M. HUTTER, JR., MD: So if they quiet down, they're clinically stable, no big ST depression, it would be okay to wait until 6:00 in the morning. Don't wait another day, but do them the next morning. But put them on IIb/IIIa in addition to the heparin while you're waiting for the six hours. Is that fair?

CHRISTOPHER GRANGER, MD: Yes. Or even if it's a Saturday, it's fine to wait until Monday if they're stable.

ADOLPH M. HUTTER, JR., MD: You would wait until Monday? I think I'd push you on that one. I think I'd push you on that one. What do you think, Dean?

DEAN J. KEREIAKES, MD: Well, we do the in-house patients on Saturdays. Now, if they come in Saturday afternoon or Saturday night, honestly, and they're quiet, they are treated medically, aggressively, and then they're cathed first thing Monday morning.

ADOLPH M. HUTTER, JR., MD: Okay, and you'd do the same.


ADOLPH M. HUTTER, JR., MD: That's exactly what you said. Well, gentlemen, that's a very nice update. Thank you very much.


DEAN J. KEREIAKES, MD: You're welcome. Thanks for having us.

ADOLPH M. HUTTER, JR., MD: And thank you for joining us. I'm Dolph Hutter.

Related References/Reading:

1. Gibler WB, Cannon CP, Blomkalns AL, et al. Practical implementation of the guidelines for unstable angina/non-ST-segment elevation myocardial infarction in the emergency department: a scientific statement from the American Heart Association Council on Clinical Cardiology (Subcommittee on Acute Cardiac Care), Council on Cardiovascular Nursing, and Quality of Care and Outcomes Research Interdisciplinary Working Group, in Collaboration With the Society of Chest Pain Centers. Circulation. 2005 May 24;111(20):2699-710.

2. Ryan JW, Peterson ED, Chen AY et al. Optimal timing of intervention in non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) Registry. Circulation. 2005;112:3049-57.

3. Fox KA, Goodman SG, Anderson FA Jr, et al., on behalf of the GRACE Investigators. From guidelines to clinical practice: the impact of hospital and geographical characteristics on temporal trends in the management of acute coronary syndromes. The Global Registry of Acute Coronary Events (GRACE). Eur Heart J. 2003 Aug;24(15):1414-24.

4. ACC/AHA Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction-2002: Summary Article. Circulation. 2002;106:1893.