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, let’s start out with
you. You’re an ER doc. What’s 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 that’s what it’s all geared to, and although we’re going to talk
about markers, we can’t forget the fact that this is EKG and history and
physical first. That sometimes is all you need, and when it’s obvious you
don’t need a test.
DOLPH HUTTER, MD:
Right.
FRANK PEACOCK, MD: So
if they’re having a STEMI, an ST-segment elevation
MI, we don’t need to have the marker conversation; you just go on to the cath lab. So we’ve already defined a population that…
DOLPH HUTTER, MD: And
even a non-STEMI with ST changes and classical history, that’s pretty
straightforward.
FRANK PEACOCK, MD:
Yes, and so markers help you when it’s less obvious, so that’s 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 that’s 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 it’s 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, it’s about between four to six hours after onset of pain that these
markers both become elevated. In the early setting this doesn’t make much of
a difference.
DOLPH HUTTER, MD:
Okay. That’s a very good point, and that’s the difference in the assays now.
MAGNUS OHMAN, MD:
Right.
DOLPH HUTTER, MD:
Okay, so you would give both.
MAGNUS OHMAN, MD:
Yes.
DOLPH HUTTER, MD:
Would you give both?
FRANK PEACOCK, MD: We
do, and would also get brain natriuretic peptide
(BNP) added to that mix.
DOLPH HUTTER, MD:
Okay.
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:
We’ve gone exclusively to troponin, and unless
we’re looking for reinfarction, where we were, creatine kinase–myocardial band
(CK-MB) separately. We’ve found that with the highly sensitive troponin assays that we can at least reliably exclude
necrosis with serial measurements through 69 hours, so we’ve eliminated
partly for cost reasons, even though it’s a modest cost.
DOLPH HUTTER, MD:
Well, that’s a good point. So the advantage of troponin
is it’s very specific, isn’t 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. That’s
the re-infarction picture, isn’t it?
JAMES DE LEMOS, MD: Right.
DOLPH HUTTER, MD: You
don’t think it’s cost-effective to do it. Other people do. I guess we use
both also, soyou could do
it either way. Is that fair? They’re 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.
DOLPH HUTTER, MD:
Right.
MAGNUS OHMAN, MD: In
cardiovascular medicine, the things that –
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.
DOLPH HUTTER, MD:
Yes.
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:
It’s less of an issue but it’s 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 “demand injury recurrent.”
MAGNUS OHMAN, MD:
There you go. I like that. And then…
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 it’s 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 injured…
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:
It’s 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, don’t forget to look at V1, V2, V3 for right ventricular strain pattern in these people,
pulmonary. That’s a very good point. So troponin
is not just acute myocardial infarction; it’s these other things that you’ve
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 that’s 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. It’s used as an exclusion of ischemia. It’s not a necrosis marker and
the mechanism is really poorly worked out, and it remains to see if that’s
going to be widely adopted. It certainly won’t 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, that’s an interesting marker, and as you said, this is an ischemia
marker, not a necrosis marker.
FRANK PEACOCK, MD:
Correct.
DOLPH HUTTER, MD: So
we’ll 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 doesn’t 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, it’s a
dominant marker of subsequent death and heart failure. I think the big
problem is we just don’t know what to do with the information yet. There’s –
that piece is missing in terms of what do you do with the patient that’s troponin negative and has a BNP elevation without heart
failure?
DOLPH HUTTER, MD:
Let’s stay with the BNP because I think that’s a very important marker. Now,
Magnus, what’s the mechanism of raising a BNP?
MAGNUS OHMAN, MD:
Well, it’s felt to be due to the distension of the left ventricle (LV) and left atrium in heart failure
that actually releases…
DOLPH HUTTER, MD: And
mostly the LV. Isn’t it mostly the LV or left atrium also?
MAGNUS OHMAN, MD:
Yes, I think both.
DOLPH HUTTER, MD:
Okay.
MAGNUS OHMAN, MD: And
I think that’s 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 there’s a lot of
muscle that’s unhappy, and so I guess it’s the same thing. It’s 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 it’s 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 it’s something that causes LV unhappiness.
DOLPH HUTTER, MD:
Well, I’m glad you like the term because, you know,
if the LV is unhappy your prognosis is going to be worse, so I
think that’s the bottom line.
What about point of care? You know, the guy comes in, he’s 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:
It’s about 15 minutes with some of the point-of-care platforms. Now, that’s
sort of misleading, though, because that’s 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 doesn’t jump out of
the patient. It’s 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 it’s in the doctor’s
brain.
DOLPH HUTTER, MD:
Yes.
FRANK PEACOCK, MD:
But that’s a big improvement over what we can do with central lab strategies.
So there’s a huge push as we’ve 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 it’s 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, you’re 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 there’s 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 you’re high risk and we’re
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:
Yes.
DOLPH HUTTER, MD:
Okay.
FRANK PEACOCK, MD:
But the test time itself is only 15 minutes.
DOLPH HUTTER, MD: No,
I understand that, yes.
FRANK PEACOCK, MD:
It’s the process that’s so…
DOLPH HUTTER, MD: And
you get all three right up front.
FRANK PEACOCK, MD:
Yes.
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 actually…
DOLPH HUTTER, MD: So
if they’re talking about an hour, you get there in an hour and 20 minutes or
something like that?
MAGNUS OHMAN, MD:
Right, and that’s probably because our lab is actually right next door to
the…
DOLPH HUTTER, MD: So
it’s a logistics thing.
MAGNUS OHMAN, MD:
Exactly.
DOLPH HUTTER, MD:
Okay, that’s a good point. Good. Now, and can you get qualitative or
quantitative with point of care?
FRANK PEACOCK, MD:
Both.
DOLPH HUTTER, MD: You
can get quantitative also?
FRANK PEACOCK, MD:
Yes.
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 Parkland’s 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 we’ve looked at the logistical issues and decided that point of
care really won’t 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:
That’s 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 they’re pretty comparable?
FRANK PEACOCK, MD:
It’s really a systems…
DOLPH HUTTER, MD: It
depends on the system.
FRANK PEACOCK, MD:
It’s what specific system you’re 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. That’s
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 we’re 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 we’ve 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 don’t measure BNP routinely, but I
think given the associations of BNP with LV dysfunction and more extensive
coronary disease, I think it’s reasonable to consider cathing
those folks looking for a compelling anatomy if they’re troponin
negative but have an elevated BNP.
DOLPH HUTTER, MD:
Okay.
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.
DOLPH HUTTER, MD: How
about 2:00 in the morning?
MAGNUS OHMAN, MD: No
data yet. And, in fact, I’m 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:
I’ll come back to that because, what have you got, if any one of these markers
up would you mobilize for –
FRANK PEACOCK, MD: I
think we’re consistent with everybody else at this table in that troponin drives the situation predominantly, and when BNP
is elevated we recognize that it’s a risk marker and is associated with a
really bad short-term prognosis, but I’m 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 that’s a very fair summary, and I’m glad I pushed you on that a
little bit because I think there are situations – and I hope you guys would
agree – 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 we’re talking about the place
where you only have the markers and there there’s no data. Even a BNP there’s
no data that you’ve got to go that night, but we would cath
them but the next morning would be reasonable. Is that a fair summary?
MAGNUS OHMAN, MD: 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.
MAGNUS OHMAN, MD:
Right.
DOLPH HUTTER, MD: Let
me ask you, are there any other markers, and I personally, we use the troponin and CPK. We’re studying the role of BNP in acute
coronary syndrome. We don’t 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.
DOLPH HUTTER, MD:
Good.
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 it’s certainly prognostically very
important. So those what I call general markers are very important in the overall
assessment. We mustn’t 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:
It’s complicated, I think, and difficult to interpret in the early period
because it’s 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 it’s 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, we’ve been looking at MPO, myeloperoxidase,
and the data we have right now is somewhat limited just by it hasn’t 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:
It’s sort of a disease marker. It’s myeloperoxidase.
It’s a plaque and white cell product and so you can measure that to give you
an idea of burden. And so it’s been valuable prognostically
in determining patients with suspected acute coronary syndromes, negative troponins, for risk stratification. Whether it’s a real
out marker, we just don’t know yet.
DOLPH HUTTER, MD: And
it’s 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 that’s 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.
DOLPH HUTTER, MD:
Okay.
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 it’s
fairly difficult to measure, the data are a little inconsistent, and it’s got
a long way to go before it’s 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 we’ll see. Anything else coming
along?
MAGNUS OHMAN, MD:
Well, I don’t 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 we’re 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. That’s very
enlightening and I think a pretty good consensus. It’s been a lot of fun.
Thank you.
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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.
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10;103(14):1832-7.
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