Signals from the injured heart: the role of cardiac markers in managing patients with acute coronary syndrome.
Just four hours ago, a 55-year-old executive was having dinner at his Country Club. Having felt nauseated and in distress for the past two hours now, the man, at 1 a.m. notes an undefined pain in his upper chest. Are these symptoms the result of the rich turtle soup he ordered upon the insistence of a pushy waiter, the three martinis he consumed during the cocktail hour ... or could this be the Big One? he worries as he wakes up his wife.
After debating the issue for the next hour, the executive and his wife decide to go to the emergency room of a local hospital, where they are greeted by the attending physician on duty. After obtaining a brief history, a quick physical exam, an EKG, and a blood draw, the physician writes "Rule out AMI" on the man's chart.
This same scenario - or at least a very similar one - repeats itself 6 million times a year in this country.
Cardiovascular disease is the number one killer in the U.S., and acute myocardial infarction (AMI) is its most common presentation. Approximately 1.5 million Americans suffer from AMIs annually, with a death rate of half a million. Half of these deaths occurs before the patient ever reaches the hospital. About 1.25 million of the 6 million "Rule out AMI" patients do, in fact, suffer from this condition. Conversely, 80% of the "Rule out AMI" patients do not have a heart attack. The clinical challenge is one of distinguishing patients with acute coronary syndrome who, in fact, have AMIs from those who don't. This article presents this problem from a clinical as well as an economic perspective.
Defining the diagnostic problems
First some definitions. A myocardial infarction is the destruction of sufficient heart tissue that causes significant clinical, electrical, and/or biochemical changes in the body. The classic World Health Organization (WHO) definition of an AMI consists of a history of unrelenting, crushing chest pain; EKG changes (e.g., a Q wave on an electrocardiogram recording); and an increase in the serum concentration of cardiac markers in the blood, particularly the elevation of CK-MB in serum.
Unfortunately, the classic three-legged stool supporting the AMI diagnosis is a bit wobbly. For starters, a patient's history often is misleading and occasionally not definitive. Further, gastrointestinal symptoms can masquerade as cardiac pain. The silent AMI frequently is seen in diabetics and in the elderly, in whom there may be accompanying neurologic deficits. Thus, relying on patient history can lead to false-positives or to false-negatives.
In addition, the EKG is nondiagnostic in 50% of AMI patients upon admission to the emergency department. Finally, the CK-MB gold standard has become a bit tarnished in recent years. This is due to the realization that skeletal muscle disease also can lead to an elevated CK-MB independent of an AMI and that elevations in CK-MB are somewhat transient and thus do not span the wide period of time needed to observe the patient with acute coronary syndrome. Certainly the scene has been set to search for the perfect cardiac marker to accompany CK-MB or to replace it as the new king of the AMI-diagnostic hill. The article by Donald Mercer, Ph.D., entitled "A historical background in cardiac markers," (p. 45), presents additional cardiac markers that may succeed CK-MB in that role.
Now for more definitions. Myocardial ischemia is an insufficient supply of oxygen to the heart usually related to coronary insufficiency, or decreased blood flow to the heart. Myocardial injury ranges from AMI to minor myocardial damage. Some authors use the term microinfarcts to refer to episodes of minor myocardial damage.
What is the significance of myocardial injury in patients who do not yet have an AMI? First let's define unstable angina. Angina means heart pain. Unstable angina is heart pain that continues over time. A significant number of patients with unstable angina will experience a subsequent AMI or some other adverse cardiac event. Often these patients experience myocardial injury, which then heralds a future cardiac attack.
When assessing the clinical utility of cardiac markers, one must realize that a very specific marker may diagnose correctly most patients with AMI but still may overlook many patients with myocardial injury who will experience an AMI eventually. Moreover, a more sensitive marker will detect patients with an AMI but also identify patients with minor myocardial injury who are likely candidates for a subsequent adverse cardiac event.
Accurate diagnoses a must
What are the clinical implications of diagnosing patients with acute coronary syndrome correctly? Today, a series of useful pharmacological agents (thrombolytic drugs, for instance) is available for the immediate post-infarction period. The administration of these agents, however, is associated with complications, especially hemorrhage. Presently clinical guidelines recommend their usage only when an AMI diagnosis in secure.
Typically patients diagnosed with AMI are admitted to an intensive care unit for the first few days, where they are monitored for arrhythmias, shock, reinfarction, or congestive heart failure. Further, each year about 30,000 Americans with AMIs are sent home from the hospital having been misdiagnosed. The clinical implications of undertreatment are obvious.
The opposite side of the coin is overtreatment. Here a patient who has not suffered from an AMI is kept in the hospital emergency room for a prolonged stay or is admitted for observation in the intensive care unit. These hours or days in the hospital can cost an institution a tremendous amount of money - money that is hard to come by in this age of cost-containment and managed care.
From a financial perspective, it is critical to rule out AMI as soon as possible in patients who may have symptoms of acute coronary syndrome but not an infarction.
Finally, we mustn't forget the emotional impact involved in admitting a patient to a coronary care unit who has not had an infarct. The patient, family, and friends are worried unnecessarily until they get word the next day that the extra concern was unwarranted. Making matters worse, most insurance policies include a copayment clause as well as a deductible. A patient can be obligated to pay hundreds of dollars for a short, unnecessary hospital stay.
The ideal marker
Indeed, cardiac markers play a significant role in managing the patient with acute coronary syndrome. See the accompanying figure for characteristics of the ideal cardiac marker. Following is a brief discussion on each:
Marker is cardiac specific. The major concern here is potential cross-reactivity with similar proteins from other tissues. Skeletal muscle contains many of the same proteins as does heart muscle. Thus the ideal cardiac marker must not be elevated in the serum of patients with muscle disease or muscle trauma.
Marker rises soon an infarct occurs. This is a real problem for most cardiac markers. The released protein leaves the area of cardiac injury by way of the lymphatics and enters the blood stream several hours after cardiac insult. If our business executive had entered the emergency room minutes - rather than hours - after onset of chest pain, his test results probably would have been negative if the lab relied on cardiac markers currently available.
Marker is elevated over a sustained period of time. If our patient had waited to seek treatment for several days, would his test results still be positive even if he had sustained an AMI? The ideal marker remains elevated to detect AMIs that occur many days before specimen collection.
Marker is easy to measure. Is the test done on whole blood, serum, or specially prepared plasma? Can the assay be done by many techs, day or night, or must the procedure be conducted by highly skilled personnel on the day shift?
Marker measurements have a broad dynamic range. Many markers are in the picograms per mL concentration in the serum of healthy subjects. Patients with minor myocardial injury without AMI may have values below the 0.05 ng/mL (50 pg/mL) level. The ideal marker measures values with a high degree of reproducibility at very low levels. This may be necessary to detect patients with unstable angina who eventually present with more serious cardiac complications. Also, the assay should measure values in the much higher ranges, where many AMI patients fall.
Marker allows quick turnaround of test results. For patients with acute coronary syndrome, time truly is of the essence. The rapid cardiac marker test will provide results in minutes rather than hours after the blood draw.
Diagnostic use of marker is verified by clinical studies. The astute laboratorian will request studies published in peer-reviewed journals that document vendors' claims of diagnostic sensitivity/specificity and question the outcome criteria used in the study. For instance:
* Did the investigator use WHO's definition of AMI?
* Was the CK-MB value used to identify AMI patients?
* Did the investigator consider both myocardial injury and myocardial infarction in the study?
* Was the marker used as a prognostic predictor of adverse cardiac events in patients with unstable angina?
* What cutoffs were used by investigators to evaluate the cardiac marker? Using a lower cutoff will improve the computed diagnostic sensitivity of the cardiac marker, while using a higher cutoff will improve the calculated diagnostic specificity of the marker.
It's now 6:00 a.m. Our patient is still in the ER awaiting news from his physician, who is waiting for results. If our patient is lucky, he is in a hospital that employs a lab director current on pertinent cardiac marker issues. How much do you know about this topic? Refer to Dr. Mercer's article starting on the facing page to learn the present state of cardiac markers available to the clinical lab.
RELATED ARTICLE: Characteristics of the ideal cardiac marker
* Marker is cardiac specific.
* Marker rises soon after an infarct occurs.
* Marker is elevated over a sustained period of time.
* Marker is easy to measure analytically.
* Marker measurements have a broad dynamic range.
* Marker allows quick turnaround of test results.
* Diagnostic utility of marker is verified by clinical studies.
Bernard E. Statland, a member of MLO's Editorial Advisory Board, is an independent laboratory consultant based in Nashville, Tenn.
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|Author:||Statland, Bernard E.|
|Publication:||Medical Laboratory Observer|
|Date:||Jul 1, 1996|
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