Troponin poised to trigger therapy

Faster results, earlier treatment
Chest pain centers on the move
Separating myocardial infarction from ACS

July 2000
Cover Story

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 story."

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 out."

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 therapy.

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 with thrombolysis.

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.