Bedside bull’s-eye? POC cardiac tests gaining acceptance
Dramatic confirmation of the diagnostic value of POC cardiac
markers has emerged within the past year. Yet how and where such testing
is done is determined by the complex relationships between hospital
laboratories and POC testing programs.
The need to rapidly triage chest pain patients is widely recognized,
and device manufacturers—Dade Behring, Biosite Diagnostics,
Spectral Diagnostics, and others—have produced multiple-marker
test systems to address this need. "There are several instruments
varying from qualitative to semi-quantitative to fully quantitative
that are available now for near-patient marker testing," says Kristin
Newby, MD, associate professor of medicine in the division of cardiology
at Duke University School of Medicine, Durham, NC.
The value of POC cardiac markers has been known since at
least 1997. And, during the past year, three significant trials
that involved thousands of patients were reported in Circulation
and the American Journal of Cardiology. Dr. Newby was director
of one of the largest studies, the CHECKMATE trial.1
All three studies have confirmed that using combinations of troponin
I, myoglobin, and creatine kinase at the point of care sharply increases
the ability to identify patients with myocardial infarction.
This research adds credence to September 2000 guidelines from
the American College of Cardiology and American Hospital Association,
which recommended POC testing for cardiac markers. To be clinically
useful, the guidelines say, the marker turnaround time should be
within 30 minutes—a goal difficult to achieve without using
"These data are all just starting to come to fruition," says Scott
Mader, director of professional education and development for Biosite
Diagnostics, manufacturer of the Triage Cardiac Panel. "In fact,
the maturity of the literature and these clinical guidelines studies,
combined with the evolution of technology, has really been driving
POC adoption of cardiac markers."
Backing this trend, a review of the ACC/AHA guidelines, published
a year later in Lancet (November 2001), stressed that "the
most important changes relate to the inclusion of troponin into
the risk strategy algorithm." As recently as January 2002, another
meta-analysis of the studies reaffirmed "beyond any question that
troponin-positive patients are the ones who should be treated with
new drugs and would have the highest benefit from it," says Joseph
H. Keffer, MD, chief medical officer and vice president of Spectral
Diagnostics, a Canadian firm that manufactures the Cardiac STATus
Dr. Keffer was director of clinical pa-thology at the University
of Texas Southwestern Medical School when he began evaluating troponin
and its evolution as a simple, rapid, and proven method of indicating
risk of myocardial infarction. "I was interested because it did
not require an instrument platform," he says. "Therefore, it was
a tool that could discriminate troponin conversion from CK-MB independent
of the capital investment limitations that face so many hospitals."
The market dynamic is changing, Mader says, and most new customers
who are incorporating Bio-site’s Triage product are using it at
the point of care. Improved connectivity has provided an added boost.
Bio-site’s system has been on the market for 3 1/2 years and "connectivity
in the first two years on the market was a real hindrance," Mader
Adding to the growing appeal of the system, he contends, is the
usefulness of platform technology that can conduct a variety of
assays. "In the ER, you have a variety of patients present with
acute conditions, so if you have a system in place to address the
broad needs of these patients, it becomes much more functionally
valuable at POC versus a single test."
But most hospitals, including one of the sites where the major
trials were conducted, have not yet installed cardiac markers at
the bedside. Biosite’s Triage system, for example, is now used in
about 1,000 hospitals, in some cases for toxicology, in others for
cardiac markers. But only a minority of the systems are at the point
Similarly, the 1,000 purchasers of Dade Behring’s Stratus CS locate
their analyzers in various sites in the hospital. "If you look at
small hospitals, with their emergency departments very close to
the laboratory, they don’t need to put their analyzers right in
the ED," says Hanjoon Ryu, vice president for market development
in cardiac at Dade Behring. But in a hospital with at least 300
beds, more of the installed base is in the ED or in a stat laboratory
closer to the bedside than in smaller hospitals.
"Generally, an ED bed is one of the most expensive in the hospital and limited
in number," says Mary Lou Gantzer, PhD, president of the American Association
for Clinical Chemistry and director of clinical and scientific affairs at Dade
Behring. "So the focus is on triaging patients out to radiology or the chest
pain unit so you free up the ED bed and get the patient to where the most appropriate
treatment is going to happen."
Cardiac markers are a pivotal factor in ED physicians’
decisions about treatment and resource management. "If you’re an
ED physician and you have a patient with chest pain, your decision
is really threefold," says Dr. Newby. "Do I send him home, hold
and observe him, or send him to the cardiac care unit or another
inpatient bed? Cardiac marker testing helps. If the initial tests
are negative, we might send him to the chest pain unit to just observe.
If the marker came back positive, one could make a much quicker
decision to send him to the CCU so you’d free up an ER bed quicker,
or decide to use a glycoprotein IIb/IIIa inhibitor, or perhaps send
the patient to the cath laboratory for an invasive evaluation."
In the CHECKMATE study, which used the Stratus CS, "each marker
has a specific profile of when you would expect to first see it
in the serum and when it reaches maximum sensitivity for detecting
myocardial necrosis," says Dr. Newby. "Myoglobin detects it much
earlier than CK-MB or troponin. You’d expect to find it at one to
four hours, whereas you wouldn’t expect to detect CK-MB for six
hours at the earliest, and probably not until eight or nine hours."
"We said maybe there’s an advantage to putting three different
markers together and sampling them at the same time, since they
have different profiles and since we know patients come in anywhere
from 20 minutes to two days after their symptom onset," adds Dr.
Newby. "So if we take advantage of these characteristics of markers
which detect earlier versus later, and test them all at one time
across the spectrum of patients who are presenting at different
times, maybe we’ll have an advantage in detecting patients earlier."
"We combined that philosophy with POC testing," she says, "and
asked, Do we identify patients earlier? Do we do a better job of
identifying more patients at risk? And if we identify them as marker-positive
using this multi-marker strategy, does it correlate with their clinical
outcome over 30 days?"
Each site ran its standard protocol for marker testing and CK-MB
proved to be the predominant marker test. Under the CHECK-MATE strategy,
the sites were given a protocol for testing myoglobin, CK-MB, and
troponin at baseline, three hours, six to nine hours, and, if the
patient was still under observation, sometime between 12 and 24
hours. A two-marker strategy was also prospectively defined to include
CK-MB and troponin, with the question being, How much information
does myoglobin provide?
Since the study was completed, many hospitals have adopted troponin
as their predominant marker, Dr. Newby says. "It’s becoming the
gold standard marker of choice, and there is some testing of myoglobin,
but I don’t think it’s still as widely used as we might hope based
on this study and previous ones."
"There’s still some work to be done in getting the message out
about myoglobin and how helpful it is," Dr. Newby adds.
There are other protocol variations. "The hospitals we worked
with predominantly rely on marker testing serially over time, by
a schedule similar to the CHECKMATE strategy," says Dr. Newby. "But
some hospitals also incorporate myocardial perfusion imaging as
an acute test. We don’t do it at Duke, but the Cincinnati site used
"When you have a coronary artery blockage," she adds, "you’re not getting
blood flow to an area of the heart muscle. If you inject the patient with a
radiotracer that’s dependent on blood flow to get to the heart muscle, and there’s
obstruction, or what we’d call ischemia, there’s low flow to the heart muscle,
and it shows up as an area on the imaging where none of the tracer got to. It’s
just another way, like electrocardiograms or cardiac markers, to get an assessment.
But it’s not something every hospital can do or can justify based on the volume
of chest pain they see."
Another major trial, the 90-minute exclusion study,2
demonstrated the value of near-patient testing. It found that troponin
and myoglobin can exclude cases of MI within 90 minutes. Study director
James McCord, MD, cardiology director of the chest pain unit for
the Henry Ford Hospital and Medical Centers, Detroit, initially
was interested in a multi-marker approach using myoglobin to rule
In an earlier study involving 6,000 patients, called the Smart
trial, the data suggested that myoglobin and CK-MB combined at zero
and one hour identified almost 75 percent of the MIs, or a couple
hundred patients in the study. "We said that’s interesting," says
Dr. McCord. "If you can identify three-quarters of MIs in an hour,
maybe by extending it a little further to 90 minutes or three hours,
you could identify a higher percentage."
That hypothesis was borne out. By adding myoglobin to the late-rising
markers, the researchers were able to identify 63 of 65 MIs within
90 minutes. "There were only two misses, and they were actually
two patients who by their clinical presentation would be identified
at high risk anyway, independent of the markers," says Dr. McCord.
A third major clinical study published in 2001, the Ninety-Minute
Accelerated Critical Pathway,3 also found that POC testing
of troponin I, myoglobin, and CK-MB, as part of a standard clinical
algorithm, allowed chest pain patients to be triaged accurately
within 90 minutes of presenting to the emergency department.
The Henry Ford study was conducted in the background. "The patients
had their blood tested at baseline, 90 minutes, three hours, and
nine hours, and we had the standard blood tests run in the central
laboratory," says Dr. McCord. "Those results were available to clinicians,
so clinical decision--making was based on central laboratory data.
Then at the bedside, we duplicated the CK-MB and troponin and added
myoglobin; that information was not available to the treating physician."
Even though the Henry Ford Health System performed the 90-minute exclusion
study, the system does not perform POC cardiac marker testing. The several hospitals
and clinics in the system are under a moratorium on new POC testing while standardization
is developed. "We have a ton of POC—PTT, glucose, coumadin on outpatients.
But as far as cardiac markers, that’s not going to be revisited until our moratorium
is lifted," Dr. McCord says.
Cost-effectiveness studies have convincingly documented
that in chest pain triage, the enormous expense, and therefore opportunity
for savings, relates to avoiding unnecessarily admitting to the
hospital patients who are at very low risk, says Dr. Keffer. "Once
they’re in the hospital, they all wind up with extensive and expensive
further studies, such as angiography, echocardiography, nuclear
scans, and so forth." So if a low-risk patient can be managed as
an outpatient, dollars are saved and unnecessary testing is avoided.
A 1999 study published in the Canadian Journal of Emergency
Medicine supported this assertion. The study reviewed two years
of chest pain patient management in the ER at Thunder Bay Regional
Hospital, Thunder Bay, Ontario. The findings: The hospital achieved
net resource savings in excess of $500,000 per year since the cardiac
marker tests were introduced. The director of emergency services
reported that the hospital saved approximately $10 of inpatient
resources for every $1 invested in POC testing in the emergency
Would such savings be unique to Canada’s government-sponsored
health system? The reverse is true, Dr. Keffer says. Cardiac marker
testing has produced more savings in the United States because the
Canadian approach to chest pain is typically much less aggressive
and involves a less invasive pattern of care. But Dr. Keffer predicts
that will change.
"The American approach is fairly accepted internationally to be
more effective as a result of the prospective randomized trial called
the TACTICS study, which contrasted conservative management with
aggressive, invasive management," says Dr. Keffer. The study4
found that improved outcomes are achieved only in patients who are
troponin-positive. "So the cost-effectiveness story continues to
be reaffirmed," he says. "If you know which patients are experiencing
confirmed myocardial necrosis, using objective tools like biochemical
markers, you can place your resources in the more appropriate group."
Ryu, of Dade Behring, sees three fundamental customer needs in
the POC cardiac marker market. One is assay performance. "They really
like to have better sensitivity and precision in cardiac testing,"
he says. The second is rapid turnaround time. "And the third," he
says, "is convenience and quickly getting superior results at the
time they want." While these may not be controversial, manufacturers
have taken different approaches to reporting results.
Dr. Gantzer, for example, advocates a quantitative test like Dade’s
over the qualitative instruments because, she says, it gives a more
realistic picture of a patient’s status. And, "since we have all
three of the markers, you’re more likely to be able to monitor that
patient because each marker has a different time to positivity if
the patient is suffering an MI." Patients generally don’t come into
the ED at the same point in time into their chest pain, and they
can’t always pinpoint when the pain began, she adds, so the clinician
can’t be sure which marker will be most useful.
Dr. Keffer, on the other hand, contends that Spectral’s qualitative
test is more helpful. "In ER chest pain triage," he says, "the decision
is whether the patient is high or low risk. That’s a dichotomous
categorization. Once they’re higher risk, then they need to be admitted
and hospitalized and followed. And by all means, we recommend that
when they’re admitted they get quantitative levels and are followed
serially over the next several days because the highest peak is
the best indication of the level of risk."
"But you don’t know what the level means at the time you see them in the ER,"
he adds, "because you don’t know whether it’s on the way up or down." For example,
patients sometimes present on the tail end of a new infarct with a new episode
of chest pain. "Let’s say the test says it’s a 1 or 2. You don’t know if that’s
the peak for that event or whether it’s on its way up to 20 or 100," says Dr.
Keffer. "So we simply advocate our use of a qualitative in that initial evaluation
of the patient in the ER, because you can get rapid performance and rapid risk
Regardless of how results are reported, turnaround time
in the stat laboratory can be a hindrance to rapid triage. "People
in the laboratory will talk about a mean TAT of 45 minutes. That
simply means that 50 percent are longer and there’s a significant
number that take over 60 minutes," says Craig C. Foreback, PhD,
senior lecturer in the clinical laboratory science program at the
University of Wisconsin Medical School and a co-author of the -90-minute
exclusion study. "So the percentage of time you’re meeting the goal
of one hour may be only 75 or 80 percent. What do you do about those
patients? That’s where POC testing comes in."
But whether ED personnel can use POC cardiac markers optimally
is not yet known. "One thing everybody talks about," says Dr. Foreback,
"is when people order tests in the ER, they wait for the results
to come back, they do something else, then get sidetracked, and
think, oh yeah, I have to check on these results." The initial study
at Henry Ford focused on the efficiency of the testing. "The next
step would be to see if that improved turnaround time—not
just the fact that results are available sooner, but whether they
are more readily available to the caregivers right at the patient,"
At the University of Wisconsin, no cardiac testing is performed
outside the central laboratory, and no one appears to be pushing
for it. "So I think it varies from institution to institution,"
says Dr. Foreback. "And it might have something to do with what
people ultimately think can be done with POC in terms of reducing
this diagnostic window."
"What we’re finding as a point-of-care company," says Biosite’s
Mader, "is the same thing that the investigators are finding, and
that is that being able to demonstrate something in clinical trial
and being able to put it into clinical practice are two different
things. Implementation in the hospital requires the concerted effort
of multiple disciplines, and I don’t think the community has been
as efficient as it would like to be in encouraging emergency medicine,
administration, cardiology, and clinical chemistry to work together
to make the processing more efficient."
Dr. Keffer maintains that the laboratory community nationwide
has resisted POC testing. "When I was director of laboratories at
Parkland Memorial Hospital in Dallas, we instituted about 20 different
POC tests," he says. "They were all critically related to key medical
decision--making, but we never had a single test that we -didn’t
have resistance from the laboratory staff fearing that they would
lose their franchise."
"You’ll find it veiled, in various fashions, with the idea that
one can do better in the central laboratory, and that was true for
years with glucose," he adds. "Everyone knew that fingerstick glucose
was not as precise or as sensitive as a laboratory test, but it
was only the advance of fingerstick glucoses that permitted tight
diabetic control five times a day." The same, he suggests, applies
to other tests, such as pediatric strep throat or pregnancy tests
before an x-ray—the immediacy of the results tends to outweigh
the difference in accuracy.
Resisting change, he notes, is common throughout medicine and
is not unique to the laboratory. "We see the same thing among physicians-cardiologists,
lots of them, still clinging to CK-MB in making a diagnosis," he
Guidelines alone are not enough, Dr. Keffer emphasizes. "I’ve
analyzed the literature to date as to guidelines adoption and resistance,
including things as notable as the National Institutes of Health
consensus conference, which was systematically published over the
years in the Journal of the American Medical Association
and had essentially no effect."
It’s not shocking that people in medicine are slow to change,
he says. "You have to work the system to have them migrate to new
paradigms." More has been learned about guidelines in recent years
and they now tend to be evidence-based, "not someone’s best estimate
but based on solid evidence from prospective, randomized trials
when possible," says Dr. Keffer.
More important, he adds, "we now know that to advance medical
guidelines, we need to actively disseminate and sell them to clinicians"-in
the same way, for example, that the pharmaceutical industry does
drug detailing. Inspired by industrial concepts of continuous quality
improvement, the most academic of groups in Europe and the United
States are now issuing guidelines under special programs, such as
the AHA’s Get With the Guidelines, or GWTG. For the ACC, the equivalent
is the Guidelines Adoption Program, which is being used to promote
better cardiac diagnosis and management.
One of the leading items on the research agenda is improved markers.
Says Duke’s Dr. Newby: "We already know, and some of the other recently
completed research we’ve done suggests, that we can use the results
of troponin testing at least to help us make decisions about using
other therapies like glycoprotein IIb/IIIa inhibitors or low-molecular-weight
heparin or early invasive testing." The next approach will involve
asking, "Does multi-marker testing extend beyond high-risk patients
to chest pain units and acute coronary symptoms? Ultimately, we’re
looking for even earlier markers of ischemia, before myocardial
necrosis occurs. Right now even though myoglobin is early, it’s
there only if the heart muscle has died."
Dr. McCord and others would like to see more research on cost-effectiveness.
"When the technology first came out, there were several criticisms—one
that it wasn’t qualitatively as good as the central laboratory.
These now are approved FDA devices, so that’s sort of a moot issue,"
he says. The only other argument is cost, he adds. "And if you look
at the per-unit blood test, it would be more expensive."
"But the big question is, Can POC testing improve the process
enough by having faster information to make it monetarily attractive?
Some institutions may save an hour, depending on what their turnaround
time is, others may save two hours," he says. "No one has implemented
the technology and done a good study of before and after."
The other question, he adds, is, Can you improve patient outcomes by identifying
high-risk patients and instituting appropriate therapies more quickly? "Most
cardiologists will tell you they know of many cases where if they had had the
information one or two hours earlier, it would have had a big impact clinically
on the patient, but those are anecdotal," he says.
Now that studies have demonstrated the value of POC cardiac
markers, researchers need to determine their impact on patient outcomes,
says Dade Behring’s Dr. Gantzer. "If you look at the CHECKMATE study,
you can certainly identify positive patients much earlier with bedside
testing and detect more of them with first measures versus later
serial measures. The question then becomes, How rapidly can the
ED staff adjust to having results available earlier and really begin
triage earlier? The study has demonstrated the potential. Now we
want to go beyond it and say, If we start treatment earlier, do
we see the improvement we expect in patient outcomes? For example,
are they in the hospital less time? Do they suffer less cardiac
damage? Do they have less serious sequelae after their admission
to the ED?"
Biosite has done a lot of research in this area and has concluded
that clinical chemistry is the "linchpin of making POC happen successfully,"
Mader says. "We find that as testing moves outside the physical
domain of the laboratory, the laboratory takes on an even greater
role and responsibility in this area." With POC cardiac marker testing,
"the only thing that’s really changed is that the speed of results
has become much more ’real-time’ for clinicians; in fact, the laboratories’
purview will always be critical to this testing."
"This is why," Mader says, "technology needs to evolve in such
a way that LIS connectivity is always accomplishable, that quality
assurance is always seamless, and that industry learns to work through
the laboratory rather than around the laboratory."
Anne Paxton is a writer in Seattle.