Multi-Marker Strategies for the Rapid Diagnosis of ACS (12/2005)

DOLPH HUTTER, MD: Hello, I'm Dolph Hutter. Welcome to the American
College of Cardiology Conversations with Experts. In this program, we will discuss multi-marker strategies for the rapid diagnosis of acute coronary syndromes. Joining me to talk about this topic is Dr. James De Lemos, Associate Professor of Medicine at the University of Texas Southwestern Medical School in Dallas, and Dr. Magnus Ohman, Associate Professor of Medicine and director of the program for Advanced Coronary Disease at the Duke University Medical Center in Durham, North Carolina, and Dr. Frank Peacock, Vice Chief of Emergency Medicine and Medical Director of the Event Medicine program at the Cleveland Clinic Foundation in Ohio. Gentlemen, thank you for joining me. And Frank, letís start out with you. Youíre an ER doc. Whatís your approach to the patient that comes in with acute coronary syndrome? How do you do your initial evaluation?

FRANK PEACOCK, MD: Okay. Well, you know, the ER is the land of risk stratification for chest pain, and thatís what itís all geared to, and although weíre going to talk about markers, we canít forget the fact that this is EKG and history and physical first. That sometimes is all you need, and when itís obvious you donít need a test.


FRANK PEACOCK, MD: So if theyíre having a STEMI, an ST-segment elevation MI, we donít need to have the marker conversation; you just go on to the cath lab. So weíve already defined a population thatÖ

DOLPH HUTTER, MD: And even a non-STEMI with ST changes and classical history, thatís pretty straightforward.

FRANK PEACOCK, MD: Yes, and so markers help you when itís less obvious, so thatís a population we talk about during our rule-out, where they come in and, because of the insensitivity of the classic necrosis markers, we end up doing serial markers. And then if those are still negative we end up going with some kind of profusion imaging or stress testing of that nature.

DOLPH HUTTER, MD: Okay, now thatís a good overall view. Magnus, let me start with you now. What markers are we talking about? Which markers should we be doing in the ER?

MAGNUS OHMAN, MD: Well, we typically measure CK-MB and troponin. Those are the two markers that we have routinely used. CK-MB, you can argue, may not be needed once we had the troponin data, but in general, most hospitals in the
United States at least measure both, particularly because the CK-MB can measure reinfarction later on, so itís sort of a useful marker to have. Those two markers are important.

DOLPH HUTTER, MD: Does it peak earlier? Does the CPK come out earlier?

MAGNUS OHMAN, MD: No. In fact, with the newer, more sensitive troponin assays, itís about between four to six hours after onset of pain that these markers both become elevated. In the early setting this doesnít make much of a difference.

DOLPH HUTTER, MD: Okay. Thatís a very good point, and thatís the difference in the assays now.


DOLPH HUTTER, MD: Okay, so you would give both.


DOLPH HUTTER, MD: Would you give both?

FRANK PEACOCK, MD: We do, and would also get brain natriuretic peptide (BNP) added to that mix.


FRANK PEACOCK, MD: Because it gives us additional prognostic information in the non-STEMI population.

DOLPH HUTTER, MD: So, James, do you use both? Do you use creatine phosphokinase (CPK) and troponin?

JAMES DE LEMOS, MD: Weíve gone exclusively to troponin, and unless weíre looking for reinfarction, where we were, creatine kinaseĖmyocardial band (CK-MB) separately. Weíve found that with the highly sensitive troponin assays that we can at least reliably exclude necrosis with serial measurements through 69 hours, so weíve eliminated partly for cost reasons, even though itís a modest cost.

DOLPH HUTTER, MD: Well, thatís a good point. So the advantage of troponin is itís very specific, isnít it? And it goes up earlier than we used to think. It stays up for a while, so the advantage of the CPK, it goes up, comes down, and get more pain, goes back up again. Thatís the re-infarction picture, isnít it?


DOLPH HUTTER, MD: You donít think itís cost-effective to do it. Other people do. I guess we use both also, soyou could do it either way. Is that fair? Theyíre both reliable, troponin being more specific.
Let me just quick ask any one of the three of you, what about false troponin elevations? Do you want to just list the things that could do that?

MAGNUS OHMAN, MD: Well, the most common things, and of course, we have to separate out the presence of the clinical acute myocardial infarction and ongoing myocardial necrosis that occurs in other conditions.


MAGNUS OHMAN, MD: In cardiovascular medicine, the things that Ė

DOLPH HUTTER, MD: Specifically, a good example is myocarditis.

MAGNUS OHMAN, MD: Well, myocarditis would be a perfect example, but when you see them in the emergency department, that entity tends to be different clinically.


MAGNUS OHMAN, MD: But the two ones that come up pretty frequently is congestive heart failure, particularly in people with ischemic cardiomyopathy, and the other one is hypertensive heart disease.

DOLPH HUTTER, MD: How about chronic renal failure, is that a problem?

MAGNUS OHMAN, MD: Itís less of an issue but itís still one that is a little bit hard sometimes to work with. But I want to go back to the hypertensive heart disease and the ischemic cardiomyopathy because those two conditions actually, the troponin elevation is associated with the increased risk, although in hypertensive heart disease the coronaries are frequently normal. So it is just a supply/demand issue when necrosis occurs.

DOLPH HUTTER, MD: We use the word ďdemand injury recurrent.Ē

MAGNUS OHMAN, MD: There you go. I like that. And thenÖ

DOLPH HUTTER, MD: Pulmonary edema, hypertension, a bump in the enzymes may not be a primary coronary event. It may be secondary to the demands.

MAGNUS OHMAN, MD: So in that group of patients, I think itís important to recognize that we need to separate issues of myocardial injury versus myocardial infarction or necrosis.

DOLPH HUTTER, MD: Okay. Well, thank you. I wanted to just clear that not every troponin is an acute myocardial infarction. It is an injuredÖ

JAMES DE LEMOS, MD: Another one is a pulmonary embolism, I think, should get on the table, especially with a nonspecific presentation in ECG. Not uncommonly, patients with PE will have a detectible troponin.

DOLPH HUTTER, MD: And where is it coming from?

JAMES DE LEMOS, MD: Itís right ventricle and associated with high risk, but it may create time delays and diagnostic challenges in the ED.

DOLPH HUTTER, MD: And by the way, since you mention the EKG, donít forget to look at V1, V2, V3 for right ventricular strain pattern in these people, pulmonary.  Thatís a very good point. So troponin is not just acute myocardial infarction; itís these other things that youíve mentioned.
Now, are there any other markers that are useful? Is that enough? I mean, can we just do a CPK and do a troponin? Other markers?

FRANK PEACOCK, MD: I would say thatís probably the standard and BNP is coming on. We also have ischemia-modified albumin which is FDA approved but is really not used very much. Itís used as an exclusion of ischemia. Itís not a necrosis marker and the mechanism is really poorly worked out, and it remains to see if thatís going to be widely adopted. It certainly wonít be used in a wide swath of applications other than risk stratification in an acute care situation just because of the kinetics.

DOLPH HUTTER, MD: Well, thatís an interesting marker, and as you said, this is an ischemia marker, not a necrosis marker.


DOLPH HUTTER, MD: So weíll see how that sorts out. Now, you mentioned BNP. What about BNP, gentlemen, is that an acute marker? Should we be looking at that acutely?

JAMES DE LEMOS, MD: It doesnít look like it will work as a diagnostic marker for ACS because only a proportion, maybe half of patients with an ACS event, will have detectable elevation in BNP. On the other hand, it seems to be an incredibly powerful prognostic marker so it has a great value for risk stratification. And really, when you rank it versus the other variables including troponin, C-reactive protein and other markers, itís a dominant marker of subsequent death and heart failure. I think the big problem is we just donít know what to do with the information yet. Thereís Ė that piece is missing in terms of what do you do with the patient thatís troponin negative and has a BNP elevation without heart failure?

DOLPH HUTTER, MD: Letís stay with the BNP because I think thatís a very important marker. Now, Magnus, whatís the mechanism of raising a BNP?

MAGNUS OHMAN, MD: Well, itís felt to be due to the distension of the left ventricle (
LV) and left atrium in heart failure that actually releasesÖ

DOLPH HUTTER, MD: And mostly the LV. Isnít it mostly the
LV or left atrium also?

MAGNUS OHMAN, MD: Yes, I think both.


MAGNUS OHMAN, MD: And I think thatís the sort of main mechanism for the elevation of this marker. I see it a little bit different than Jim does, and that is that we have recognized for years on the physical exam or physical diagnosis that indeed heart failure is a bad player. This is just a marker that picks it up for us where our clinical acumen may not be as good as they used to be, and I think that in a way we need to think about this marker to tell us that this is a patient with a high risk, that we need to be much more aggressive with, if the clinical diagnosis is right.

DOLPH HUTTER, MD: Yes, I kind of look at BNP as a marker of
LV unhappiness, a stretch if you will, not so much just dilatation but stretch. It could be acute, an acute ischemia, a positive exercise test. If you have a high BNP thereís a lot of muscle thatís unhappy, and so I guess itís the same thing. Itís not a marker of injury, not a marker of ischemia, but a marker of LV dysfunction primarily, less so in the RV, some in the atrium also, so itís an LV functional marker. Is that a fair summary, do you think?

JAMES DE LEMOS, MD: I like that concept of LV unhappiness because I think the problem with BNP is that there are multiple potential causes of BNP elevation, all of which are bad for the patient. So in an individual it can be really hard to sort out what the cause of BNP elevation, but generally itís something that causes
LV unhappiness.

DOLPH HUTTER, MD: Well, Iím glad you like the term because, you know, if the
LV is unhappy your prognosis is going to be worse, so I think thatís the bottom line.
What about point of care? You know, the guy comes in, heís got the pretty suggestive history, not 100%, EKG is, you know, not very diagnostic. How fast can we get some of these markers back?

FRANK PEACOCK, MD: Itís about 15 minutes with some of the point-of-care platforms. Now, thatís sort of misleading, though, because thatís the lab time, and when this has been looked at the time from the door until the physician can operate on the information is much longer because, you know, the blood doesnít jump out of the patient. Itís got to be, the patient has to be naked and their blood has to be drawn and be put in a machine. It takes about an hour from door to the brain, from the time the patient hits the door until itís in the doctorís brain.


FRANK PEACOCK, MD: But thatís a big improvement over what we can do with central lab strategies. So thereís a huge push as weíve begun to understand the time sensitivity of acute coronary syndromes that we should be doing more just because of the increased speed to diagnosis.

DOLPH HUTTER, MD: Right, and itís a decision for the cath lab.

FRANK PEACOCK, MD: And since markers are becoming such a driver, that speed has become important.

DOLPH HUTTER, MD: So you see, you get your history, youíre drawing the blood at the same time as you do an EKG, I guess now, right?

FRANK PEACOCK, MD: Yes, and actually we do it all right up front. You walk in the door, before the doc even sees the patient thereís a troponin, a BNP and an EKG done, and we use that to decide who goes back into the room next, because if one of those is up, obviously youíre high risk and weíre headed to the cath lab.

DOLPH HUTTER, MD: And how long does it take? You said about an hour. Do you think all the tests, troponin, CPK, BNP, also point of care?



FRANK PEACOCK, MD: But the test time itself is only 15 minutes.

DOLPH HUTTER, MD: No, I understand that, yes.

FRANK PEACOCK, MD: Itís the process thatís soÖ

DOLPH HUTTER, MD: And you get all three right up front.


DOLPH HUTTER, MD: Okay. What do you guys do, Magnus?

MAGNUS OHMAN, MD: Well, at Duke we tend not to use point of care. What our chemistry laboratory has done is really with the guideline that NHLBI put out a while back on having to have the time to diagnosis sort of shortened. They have actually taken on task to really get that time down. So for us, the time between getting it from the lab and getting it from point of care is really not all that different, maybe 20 minutes.

DOLPH HUTTER, MD: Oh, really?

MAGNUS OHMAN, MD: Yes, and actuallyÖ

DOLPH HUTTER, MD: So if theyíre talking about an hour, you get there in an hour and 20 minutes or something like that?

MAGNUS OHMAN, MD: Right, and thatís probably because our lab is actually right next door to theÖ

DOLPH HUTTER, MD: So itís a logistics thing.


DOLPH HUTTER, MD: Okay, thatís a good point. Good. Now, and can you get qualitative or quantitative with point of care?


DOLPH HUTTER, MD: You can get quantitative also?


DOLPH HUTTER, MD: Okay. As reliable as a regular lab?

FRANK PEACOCK, MD: It depends on the system, but there are some point-of-care systems that are as good as lab systems nowadays.

DOLPH HUTTER, MD: Okay, all right. Now, what do you guys do?

JAMES DE LEMOS, MD: Well, I work mostly in
Parklandís Hospital Emergency Room that is a bit of a zoo, so for us the lab turnaround time is among the lesser factors that cause us patient delay. So weíve looked at the logistical issues and decided that point of care really wonít offer us much in terms of patient turnaround time. So I think it highlights that three different systems have, you know, that the logistical issues in many cases dominate the point-of-care decision.

DOLPH HUTTER, MD: Thatís an excellent point because both of you are using laboratory because you have the logistics worked out, and of course, you do get the quantitative. Do you think the lab is more reliable in general than point-of-care testing or do you think theyíre pretty comparable?

FRANK PEACOCK, MD: Itís really a systemsÖ

DOLPH HUTTER, MD: It depends on the system.

FRANK PEACOCK, MD: Itís what specific system youíre using, because there are lab systems that are less reliable than others and there are point-of-care systems that are better than others, and so you have to head-to-head comparison it. Thatís what your laboratorians are for.

DOLPH HUTTER, MD: Now let me go back to the decision for the cath lab. Obviously we know high-risk patients, they have the classical syndrome, they have ST changes, these are high risk, recurrent angina, but weíre not even talking about recurrent angina just coming in, and markers. Any one of these markers is elevated, do you send them to the cath lab or only troponin? Or how do you guys decide, James? The EKG is not there but the marker is there.

JAMES DE LEMOS, MD: We do, you know, assuming that, I think the issue with troponin is a little more complicated because obviously weíve talked about a lot of overlap syndromes that cause troponin, so if the syndrome is suggestive of ACS and they have a detectable troponin, we send them to the lab. And I think we donít measure BNP routinely, but I think given the associations of BNP with LV dysfunction and more extensive coronary disease, I think itís reasonable to consider cathing those folks looking for a compelling anatomy if theyíre troponin negative but have an elevated BNP.


JAMES DE LEMOS, MD: The data are a little weak there, though.

DOLPH HUTTER, MD: All right, Magnus?

MAGNUS OHMAN, MD: We use pretty much the same strategy. If either the troponin or the BNP is elevated and the clinical syndrome is right, then we sort of go with the early invasive strategy, so think cath next day or that in sort of realm.

2:00 in the morning?

MAGNUS OHMAN, MD: No data yet. And, in fact, Iím not too sure that actually getting the cath lab in for doing these sort of cases, when we had the cath lab in doing primary angioplasty all night long, is really a good sort of selection of resources.

DOLPH HUTTER, MD: Iíll come back to that because, what have you got, if any one of these markers up would you mobilize for Ė

FRANK PEACOCK, MD: I think weíre consistent with everybody else at this table in that troponin drives the situation predominantly, and when BNP is elevated we recognize that itís a risk marker and is associated with a really bad short-term prognosis, but Iím not clear that the data says those people need to be rushed to the cath at 2:00 in the morning.

DOLPH HUTTER, MD: Yes, I think thatís a very fair summary, and Iím glad I pushed you on that a little bit because I think there are situations Ė and I hope you guys would agree Ė that if you do have ST changes and ongoing pain, that it is worthwhile calling the people in at 2:00 in the morning or 12:00 because six hours can make a big difference there. But weíre talking about the place where you only have the markers and there thereís no data. Even a BNP thereís no data that youíve got to go that night, but we would cath them but the next morning would be reasonable. Is that a fair summary?

Yes. I think the patient that really has no ST elevation but he could have left bundle, right bundle, he could have a lot of other things. You have to think that this is really a continuum of disease, from STEMI to non-STEMI, and these patients are probably right in the middle. And so in that group of patients, yes, an early, even 2:00 AM cath might be very reasonable to really sort out the clinical syndrome to which of those sort of highest risk category fall into.

DOLPH HUTTER, MD: Yes, and the sicker the patient the more you want to know earlier.


DOLPH HUTTER, MD: Let me ask you, are there any other markers, and I personally, we use the troponin and CPK. Weíre studying the role of BNP in acute coronary syndrome. We donít routinely do it yet. We do get it at some time. Any other markers for long-term prognosis? What about inflammation, what about diabetes? Do you routinely check that in patients that come in like the next day or something like that? What are your thoughts?

MAGNUS OHMAN, MD: I want us to remind people that there are two really fundamental diseases that are important. One is diabetes, so hemoglobin A1c and a blood sugar are very important because poorly controlled diabetes really drives poor outcomes.


MAGNUS OHMAN, MD: The other one is serum creatinine, chronic renal insufficiency are terribly important. It might not go down to an invasive strategy but itís certainly prognostically very important. So those what I call general markers are very important in the overall assessment. We mustnít forget that.

DOLPH HUTTER, MD: Eventually we want to know about the creatinine and we want to know about the hemoglobin A1C, and CRP in the acute setting, any value?

JAMES DE LEMOS, MD: Itís complicated, I think, and difficult to interpret in the early period because itís so heavily influenced by the size of the cardiac injury, so.

DOLPH HUTTER, MD: Yes, any inflammatory process was going to bump it.

JAMES DE LEMOS, MD: And I think if it has value and itís still controversial, it will be in the convalescent phase when people have recovered from the event.

DOLPH HUTTER, MD: The chronic elevation of CRP as opposed to acute, so that probably is not an acute marker, and hemoglobin A1C and creatinine is not an acute but very important, so we ought to know that information in our patients before they leave the hospital.

DOLPH HUTTER, MD: Are there any new markers coming along that we should be aware of? Frank, do you have any ideas of new markers?

FRANK PEACOCK, MD: You know, weíve been looking at MPO, myeloperoxidase, and the data we have right now is somewhat limited just by it hasnít been studied in an all-comers population, but it seems to confer decent risk stratification.

DOLPH HUTTER, MD: Let me just ask you what does it mark, what does MPO mark?

FRANK PEACOCK, MD: Itís sort of a disease marker. Itís myeloperoxidase. Itís a plaque and white cell product and so you can measure that to give you an idea of burden. And so itís been valuable prognostically in determining patients with suspected acute coronary syndromes, negative troponins, for risk stratification. Whether itís a real out marker, we just donít know yet.

DOLPH HUTTER, MD: And itís an indication more of the cellular inter fact, interaction with the plaque itself.

FRANK PEACOCK, MD: I think you could say that.

DOLPH HUTTER, MD: Yes, okay. Anything else, James?

JAMES DE LEMOS, MD: The other marker thatís getting some attention is soluble CD40 ligand (sCD40L). This is an immunoregulatory molecule but appears to be released in high quantities when platelets become activated.


JAMES DE LEMOS, MD: And there have been a couple of studies suggesting that it may help to identify high-risk patients with ACS who, and potentially those who benefit from more aggressive anti-platelet therapy. But I have to say, it looks like itís fairly difficult to measure, the data are a little inconsistent, and itís got a long way to go before itís ready for us to measure clinically.

DOLPH HUTTER, MD: So an earlier marker of platelet activation, an earlier marker of cellular activation with the plaque. Is that fair?

FRANK PEACOCK, MD: Certainly plaque.

DOLPH HUTTER, MD: Yes, or maybe just plaque alone, okay. So weíll see. Anything else coming along?

MAGNUS OHMAN, MD: Well, I donít know any specific marker but what I actually think is quite interesting now is that we have really very well-defined markers on necrosis, and what you just heard from both James and Frank is that we have now disease-specific markers that are coming. So I think what weíre going to see is that disease-specific markers, markers of myocardial necrosis, and then the outcome of all of that is heart failure, the BNP. So we have sort of this multi-marker strategy that covers the broad front line of assessing patients.

DOLPH HUTTER, MD: So a changing and evolving area.  Gentlemen, thank you. Thatís very enlightening and I think a pretty good consensus. Itís been a lot of fun. Thank you.

Related References/Reading:

1.       Bodi V, Sanchis J, Llacer A, et al. Multimarker risk strategy for predicting 1-month and 1-year major events in non-ST-elevation acute coronary syndromes. Am Heart J. 2005 Feb;149(2):268-74

2.       Morrow DA, Braunwald E. Future of biomarkers in acute coronary syndromes: moving toward a multimarker strategy. Circulation. 2003 Jul 22;108(3):250-2.

3.       de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med. 2001 Oct 4;345(14):1014-21. 

4.       Newby LK, Storrow AB, Gibler WB, et al.  Bedside multimarker testing for risk stratification in chest pain units: The chest pain evaluation by creatine kinase-MB, myoglobin, and troponin I (CHECKMATE) study. Circulation. 2001 Apr 10;103(14):1832-7.

5.       Ng SM, Krishnaswamy P, Morissey R, Clopton P, Fitzgerald R, Maisel AS.  Ninety-minute accelerated critical pathway for chest pain evaluation. Am J Cardiol. 2001 Sep 15;88(6):611-7.