Troponin poised to trigger therapy
Faster results, earlier treatment
Chest pain centers on the move
Separating myocardial infarction from ACS
William Check, PhD
As the 20th-century French philosopher Jean-Paul Sartre said, "[A] man
is always a teller of tales. . . ." Patients who come to the emergency department
with chest pain are no exception: Their first-person narratives focus on when
they initially experienced chest discomfort and what it felt like. Hal Chadow,
MD, director of the Division of Cardiology at the Brookdale University Hospital
and Medical Center and assistant professor of medicine at SUNY Brooklyn, talks
about patients who tell "a typical chest pain story" or "an atypical chest pain
If the patient is a storyteller, the emergency department physician or cardiologist
is a literary critic, whose job is to explicate the subjective experience the
patient presents and select an appropriate therapy. In trying to make medical
sense of the narrative, the physician relies on objective tools-chiefly the
electrocardiogram and measurement of the serum concentration of the MB isozyme
of creatine kinase. In a certain proportion of patients this information taken
together is adequate, particularly the 15 percent to 20 percent with unequivocal
myocardial infarction, or MI.
Also easy to manage are the patients who clearly do not have an MI. But between
these poles lie the great majority of persons who come to the ED with chest
pain. While these patients may be categorized as low-, intermediate-, or high-risk
on the basis of history, laboratory findings, and ECG pattern, a clinician trying
to decide whether a patient is actually having an evolving ischemic event may
feel like a college student trying to decipher James Joyce’s Ulysses on her
own-both lack needed guidance.
As Robert Christenson, PhD, director of clinical chemistry laboratories, professor
of pathology, and director of point-of-care testing at the University of Mary-land
School of Medicine, says, "There is a need for a more specific marker to indicate
cardiac injury than our current benchmark, CK-MB. There is some question about
CK-MB being expressed in heart that is not ischemic and certainly it is expressed
in skeletal muscle, so it lacks specificity." In the search for more specific
cardiac markers, Dr. Christenson notes, "Over the last six to seven years, troponin
I and T came to the fore. In early studies troponins showed excellent heart
specificity in patients with MI versus symptomatic patients for whom MI ruled
Several studies have amply justified troponin’s early promise. It is particularly
valuable in the 15 percent to 20 percent of patients who are apparently suffering
an acute coronary syndrome (ACS), either unstable angina (UA) or non-Q-wave
MI. These patients present with progressive or "stuttering" symptoms and a negative
CK-MB. Moreover, "they don’t have ST elevation to tell the ED doctor that they
are going to have a heart attack," says Raymond Bahr, MD, medical director of
the Paul Dudley White Coronary Care System at St. Agnes Health Care, Baltimore.
(As a result, this constellation is now being called UA/non-ST-elevation MI.)
Says Dr. Christenson, "The equivalent of the ECG monitor guiding intervention
for these patients is the troponin assay." In early studies evaluating troponin
as an indicator for MI, 20 to 30 percent of patients with unstable angina also
had elevated troponin. At first these results were considered false-positives.
But in followup studies, it turned out that such patients have an increased
risk of MI or mortality in the 30 to 45 days after discharge. As the 1999 update
of the American College of Cardiology/American Heart Association Guidelines
for the Management of Patients with Acute Myocardial Infarction state, "It is
estimated that ~30 percent of patients presenting without ST-segment elevation
who would otherwise be diagnosed with unstable angina are actually experiencing
a non-Q-wave MI when assessed with cardiac-specific troponin assays."
Now, Dr. Chadow says, any patient should be treated as high-risk who presents
with unstable angina (defined as new rest pain, increasing symptoms with less
exertion, or requiring more nitroglycerin for pain relief) and who has 0.5 mm
of ST-segment depression (some would include >3 mV of T wave inversion) plus persistently
elevated troponin. Even in the presence of a negative CK-MB result, Dr. Chadow
says, "That is still an MI. It may be called minimal myocardial damage, but it
should still be treated as MI."
The use of troponin assays has lessened to some extent the importance of the
distinction between unstable angina and non-ST-elevation MI. Acute coronary
syndrome patients will usually end up with a diagnosis of either unstable angina
or non-Q-wave MI, depending on the amount of cardiac marker released.
"What we are finding now," says Paul Heidenreich, MD, assistant professor
of medicine at Stanford University School of Medicine and director of echocardiography
at the Palo Alto VA Health Care System, "is that it may be more important to
identify high-risk people as opposed to determining whether an MI actually occurred.
We know those who have ’just’ UA can be at very high risk during the next 30
days. So probably it is more important to treat all these people similarly rather
than make this distinction."
In this context, troponin is superior to CK-MB. First, it has a higher signal-to-noise
ratio. Many patients have circulating CK-MB from skeletal muscle, Dr. Christenson
points out. But cardiac troponin is virtually zero in normals, and therefore
its background biological noise level is also virtually zero.
Second, troponin has a longer half-life, which means it gives cumulative information
about cardiac events. Troponin remains positive for 96 hours to one to two weeks
after an event, while CK-MB peaks at 12 to 24 hours and is gone by 36 hours.
If a patient has several small events or intermittent blockages over a week
or two, troponin will reveal that. "Troponin gives you a richer patient history,"
Dr. Christenson says.
Cardiac tropon-ins are markers of myocardial injury as well as myocyte death,
notes Mi-len-ko Tanasijevic, MD, associate director of clinical laboratories
at Brigham and Wo-men’s Hospital, Bos-ton. So they are more sensitive than CK-MB
in settings such as unstable angina. In the TIMI IIIb trial, Dr. Tanasijevic
says, "We were able to demonstrate that elevated levels of cardiac troponin
I measured when the patients were first evaluated predicted the risk of short-term
mortality, even in patients whose CK-MB measurements were not considered abnormally
elevated." Moreover, cardiac troponin is a quantitative predictor of risk: Data
from TIMI IIIb showed that a higher initial level of troponin presaged higher
mortality at 42 days.
Assessing troponin’s clinical benefit, Dr. Heidenreich says, "I think it has definitely
improved outcomes for these patients. It has definitely improved their short,
one- to two-month outcome, because the syndrome now is being stabilized and fewer
people overall are going on to have MIs."
Cardiac troponin assays have value beyond sharpening diagnosis: They are now
being considered as guides to therapy. "What troponins have enabled us to do,"
Dr. Chadow says, "is to identify about 20 percent more patients considered at
most intermediate-risk patients whom we now treat as high-risk and institute
therapy commensurate with high risk-glycoprotein IIb/IIIa inhibitors, aspirin
and heparin plus beta blockers and nitrates."
Use of troponin levels to guide therapy is supported by analysis of results
from several trials (CAPTURE, TIMI, PRISM, PURSUIT, FRISC) using glycoprotein
IIb/IIIa inhibitors or low-molecular-weight (LMW) hep-arins, either as primary
therapy or in conjunction with angioplasty, to treat patients with UA/non-ST-elevation
MI. In retrospective analyses, these interventions were found to improve clinical
outcomes only in troponin-positive patients. In CAPTURE, for instance, among
troponin-negative UA patients, death or nonfatal MI occurred in 0.7 percent
of placebo-treated patients and one percent of those who received abciximab
during the 24 to 36 hours pre-angioplasty. Among troponin-positive patients,
those receiving placebo had a 6.6 percent event rate, while administration of
abciximab reduced this to the placebo rate, 0.7 percent. Clearly, a positive
troponin assay identifies a high-risk subset that moreover benefits from aggressive
Dr. Christenson took part in a trial, PARAGON B, first presented at this year’s
meeting of the American College of Cardiology, that found a similar pattern.
Patients meeting criteria for acute coronary syndrome were randomized to placebo
or a glycoprotein IIb/IIIa inhibitor. "The only patients who benefited were
the troponin-positive patients," Dr. Christenson says.
Elliott Antman, MD, who has taken part in and coordinated the TIMI trials,
summarizes these assay-therapy interactions. "Two new therapies on the horizon-low-molecular-weight
heparins and IIb/IIIa inhibitors-have both been found superior to current treatments."
Dr. Antman, who is associate professor of medicine and director of the Samuel
A. Levine Cardiac Unit at Brigham and Women’s Hospital, says, "Glycoprotein
IIb/IIIa inhibitors have been tested against placebo and low-molecular-weight
heparins against placebo and unfractionated heparin. For one low-molecular-weight
heparin, enoxaparin, there is evidence of superiority to unfractionated heparin.
For the others, they are superior to placebo and equivalent to unfractionated
heparin but more convenient to use." Dalteparin is the other major LMW heparin
available in the United States. What is important, Dr. Antman continues, is
that "These new treatments are progressively more effective the more at risk
a patient is. So there is a need to identify tools for risk stratification.
One such tool is troponin testing." Studies exist showing that patients who
are troponin-positive, either troponin T or I, have a more favorable outcome
with either IIb/IIIa inhibitors or low-molecular-weight heparin than troponin-positive
patients who do not receive such treatments," Dr. Antman says. "But troponin-negative
patients do not demonstrate benefit with the new therapies," he adds.
Dr. Antman emphasizes that "troponins are only one piece of the puzzle." Also
increasing patient risk are age, whether the patient has had aspirin within
the last week, and whether a patient has multiple risk factors for coronary
disease. A patient who was troponin-negative but had a number of other risk
factors would also likely do better with the new therapies.
Dr. Heidenreich makes a similar point with respect to the ECG. "Even if troponin
is negative, if there are ECG changes suggestive of ischemia, patients have two
to four percent mortality at about three months," he says. "So even if troponin
is negative, if there are changes on the ECG, that patient must be considered
at high risk." Dr. Chadow notes that glycoprotein IIb/IIIa inhibitors for which
there is good evidence of benefit are all intravenous agents-tirofiban, integrilin,
and abciximab. (All oral glycoprotein IIb/IIIa inhibitors tested to date have
shown an early 30-day increase in mortality.) Abciximab is being studied now for
use as primary medical therapy in GUSTO IV-ACS. But the benefit of its use in
the catheterization laboratory as an adjunct to angioplasty or in high-risk patients
18 to 24 hours before intervention is well documented. However, Dr. Chadow notes,
"Glycoprotein IIb/IIIa inhibitors and angioplasty seem to be complementary, so
those patients who do best are medically stabilized first, then go on to a coronary
intervention." Ongoing now is the first head-to-head trial of two IIb/IIIa inhibitors,
TARGET, comparing abciximab versus tirofiban in the catheterization laboratory.
If used more widely, these agents may not increase total health care costs,
despite their high cost, Dr. Heidenreich suggests. Using troponin assays to
risk-stratify and target treatment, "We are able to treat earlier and possibly
discharge appropriate patients from the ED and even from the hospital," he points
out. "So although the medications themselves are more expensive, the decrease
in subsequent heart attacks and perhaps a decrease in inappropriate admissions
may be offsetting that." A number of issues remain to be settled, chiefly the
validity of troponin assays to select patients for therapy.
"Right now it is highly suggestive, but not yet proven, that you could use
troponin to guide therapy with these agents," Dr. Heidenreich says. Data showing
that the benefit of therapy with glycoprotein IIb/IIIa inhibitors and LMW heparin
was confined to high-risk patients, as determined by elevated troponin levels,
were obtained by retrospective analyses. Therapy was not actually prospectively
based on troponin values. As a result, Dr. Heidenreich says, "I don’t think
there have been enough data yet and not a specific trial to look at that question.
So many cardiologists are not yet full believers that we should use troponin
to guide treatment."
Results from one study using troponin as a prospective tool to guide therapy-GUSTO
IV-ACS-are due to be reported at the European Cardiology Society meeting this
August. In this trial, patients with UA/non-Q-wave MI (no ST-segment elevation)
and either ST depression or a positive troponin value have been randomized to
abciximab or placebo as primary medical therapy.
GUSTO IV-ACS addresses another of Dr. Heidenreich’s concerns. "Everyone is
convinced," he says, "that high-risk patients, however defined, benefit from
IIb/IIIa inhibitors and that they benefit from low-molecular-weight heparin.
But it is unclear yet whether these two agents can be used safely together."
In GUSTO IV-ACS, patients are randomly assigned to either abciximab plus dalteparin
or abciximab plus unfractionated heparin.
Dr. Bahr cites a study in progress, called EARLY, that is using troponin-positive
results to determine treatment. Half of patients are treated with a IIb/IIIa
inhibitor in the first 12 hours after presentation, while the others are treated
after 12 hours. This study asks whether reducing time to treatment in patients
without ST elevation is beneficial, as it is in typical MI patients treated
For clinical application, Dr. Heidenreich says, he would like to see trials
testing different combinations of a IIb/IIIa inhibitor, LMW heparin, and immediate
angioplasty in high-risk patients. Angioplasty plus a IIb/IIIa inhibitor has
been proven superior to angioplasty alone, but there are no data on a IIb/IIIa
inhibitor alone compared with a IIb/IIIa inhibitor plus angioplasty, he notes.
Finally, Dr. Heidenreich says, "We need better data to say how we can best
identify high-risk patients based on ECG, troponin, and maybe other clinical
factors. Almost all studies have just looked at troponin in isolation, similarly
with ECG. Very few studies have compared the two." He acknowledges that some
studies have looked at the prognostic value of troponin stratified by ECG, but
these are very few. "It would be nice," he says, "to have more data on determining
who is a high-risk patient based on ECG and troponin results together."
William Check is a freelance medical writer in Wilmette, Ill.