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The impact of marker selection and process improvements on cardiac care.

Scientific and technological advances continue to create better tools for the diagnosis and treatment of cardiac disease. These developments do not universally lead to better medicine, however. Out of habit, even physicians who stay current in their field may continue to rely on outmoded, but familiar, methods. Nor are the most accurate and reliable assays always available in hospital laboratories.

Process problems raise other questions. Has the laboratory streamlined its processes sufficiently to make a significant impact on test turnaround time (TAT)? Are physicians and laboratorians collaborating in a manner that takes full advantage of their complementary knowledge and skills? In hospitals where either of these questions is answered in the negative, even state-of-the-art diagnostic testing will not have the desired impact.


In short, responsible medicine depends on an interaction between human and scientific/technological factors. With that in mind, the following discussion considers the relative advantages and disadvantages of widely deployed cardiac markers, and then examines the process improvements that are critical to any marker's optimal utilization.

Cardiac markers in the evaluation of patients with ACS

The electrocardiograph (ECG) remains a valuable tool for evaluating patients who present in the emergency department (ED) with chest pain or shortness of breath (SOB). This diagnostic tool has severe limitations that cannot be overlooked. Although most emergency medicine physicians feel comfortable in interpreting the ECG, it is nondiagnostic in 50% of cases. An ECG can also be difficult to interpret in cardiac conditions, such as left bundle branch block, ventricular paced rhythm, and left ventriculary hypertrophy. (1-7) Emergency physicians and clinical laboratorians are thus growing increasingly dependent on biochemical markers to evaluate patients presenting with possible cardiac symptoms.

Cardiac markers are utilized in the ED in several circumstances. For patients who present to the ED with unequivocal ST elevation in the ECG, cardiac markers may be used to confirm the diagnosis of acute myocardial infarction (AMI). Their greatest utility in these situations, however, is to detect AMI at an early stage, estimate the infarct size, predict the effectiveness of early reperfusion, and prognosticate the patient's clinical condition. (8)

Cardiac markers play a much larger role in the large cohort of patients who present to the ED with either a nondiagnostic ECG or a nonST segment elevation myocardial infarction (NSTEMI). For these patients, the markers are invaluable in the diagnosis and management of acute coronary syndromes (ACS).

Among the most commonly used markers are the following:

CK and CK-MB. Levels of the creatinine phosphokinase (CK) enzyme rise in the blood within three to six hours after the onset of myocardial infarction (MI) and remain elevated for 24 to 36 hours. (9) Because of this property, CK--in combination with the ECG--has been used as a marker for the diagnosis of AMI. CK levels, however, can be elevated from causes other than myocardial injury, such as trauma or illnesses that cause hypoperfusion and skeletal muscle injury. Because of the physiologic role of CK, it is found in measurable amounts in healthy individuals. (10-13) Because the sensitivity and specificity of CK to cardiac illness are far from ideal, the cardiac community has transitioned to other assays. If CK is to be used at all, a consensus of cardiology experts recommends combining CK with either CK-MB or troponin. (14)

CK-MB, an isoform of total CK, was once considered the "gold standard" in cardiac markers for the diagnosis of MI. A large protein, CK-MB is released into circulation through the lymphatic system. Levels begin to rise about four to eight hours after myocardial necrosis and remain abnormal for 48 to 72 hours. CK-MB is relatively sensitive, but its specificity is affected by its presence in skeletal muscle. CK-MB has been used in combination with total CK to create a "CK-MB index" in an effort to increase the specificity for MI, but this provides only marginal benefit and may be misleading in cases of combined skeletal and myocardial injury.

Other limitations of both CK and CK-MB should be noted, as well. For instance, unlike troponin, these markers do not have the ability to risk-stratify and prognosticate patients with ACS. Today, we have a more sophisticated understanding of the pathogenesis and pathophysiology of ACS. We also better appreciate the need for early intervention with time-sensitive treatment. Accordingly, the deficiencies of CK and CK-MB in these areas have become more significant and the preference for "more capable" markers has grown.

The utility of CK and CK-MB is also limited by their release and persistence patterns after the onset of AMI and may result in a nondiagnostic level in some cases. They may not be elevated in chest-pain patients who present to the ED earlier than at least three hours following AMI, and may also miss patients who arrive more than 12 to 24 hours after an AMI. Because CK and CK-MB, however, can detect re-infarction that other markers may miss, they continue to be used.

Cardiac troponins. There are three isoforms of troponin: troponin C, troponin I, and troponin T. Only troponin I and T are useful for cardiac diagnosis. These proteins occur in both cardiac and skeletal muscle; however, the amino-acid sequence of the cardiac isoform is different from that found in skeletal muscle. Therefore, the cardiac troponins have a clear advantage over CK, CK-MB, and myoglobin in sensitivity and specificity for myocardial necrosis. (10,15-17) Indeed, these two troponin isoforms are now the biochemical markers of choice for evaluating patients presenting to the ED with signs and symptoms of ACS, according to a joint committee of the European Society of Cardiology (ESC) and the American College of Cardiology (ACC). (14)

The benefits of the cardiac troponins do not end there. Troponin I does not circulate in the blood of normal individuals and is 13 times more abundant in the myocardium than is CK-MB. This gives it a better signal-to-noise ratio for detecting minor amounts of myocardial necrosis. (10-13) In fact, both troponin T and I are sensitive enough to detect microinfarction that may not be apparent on the ECG or by using other cardiac markers--such as CK or CK-MB. Using troponin assays, about 30% of patients who were once classified as having unstable angina are now classified as NSTEMI. (14)

Troponin I and T can be used to prognosticate patients with ACS, as well. Studies have shown that patients with a negative troponin have a 30-day mortality rate of 5%, whereas patients with positive troponin have a 30-day mortality rate of 13%. Patients with positive troponin were also found to have an increased rate of post-AMI cardiac events compared to patients with negative troponin. (18)

In addition, troponin assays have been found to be useful in the diagnosis of pulmonary embolism (PE). The mechanism of release of troponin in this disease is thought to be due to myocardial ischemia, and microinfarction due to an imbalance between the oxygen supply and demand of the failing right ventricle. The elevation of troponin in the blood is mild and of shorter duration compared to the elevation that follows ACS. (19)

Finally, the sensitivity and specificity of troponin assays should reduce the rate of inappropriately discharging patients who have suffered an AMI, currently an unacceptable 5% to 8%. This would mean not only better and safer patient care, but also lower healthcare costs associated with inappropriate discharges. (20-21)

Keep in mind, however, that not all troponin assays perform alike. For instance, research has shown the Access AccuTnI troponin I assay (Beckman Coulter, Fullerton, CA) to be more precise and sensitive than some other commonly used assays, meaning this troponin I assay may identify more patients with poor prognosis who should be assigned to active intervention. (22)

A second study compared and evaluated 14 different troponin assays using recently established ESC/ACC recommendations. The study compared troponin concentrations at two levels. One is the 99th percentile limit claim by the manufacturer and the second is the concentration associated with a 10% CV. An ideal ratio of 10%/99th is 1.0. The results of the study revealed that AccuTnI has the best performance and achieves the lowest ratio of all troponins. (23)

Myoglobin. Among the traditionally used cardiac markers, myoglobin is considered to rise the earliest--often within two to three hours after the onset of AMI. This makes it particularly useful for early diagnosis of AMI. Indeed, it has high negative predictive value for excluding early AMI if the patient presents within four hours from the onset of his AMI symptoms. (23)

Like CK-MB, myoglobin lacks specificity for myocardial injury because it also elevates in the event of muscle injury or disease. Its sensitivity and specificity can be increased by combining it with other markers, such as CK-MB and troponin in a multimarker panel. Since myoglobin levels return to baseline values more rapidly than the other cardiac markers, it may be especially useful in detecting reinfarction.

B-type Natriuretic Peptide (BNP). It can be challenging to evaluate patients who present to the ED complaining of SOB because the differential diagnosis includes a wide range of diseases. Asthma, chronic obstructive pulmonary disease, congestive heart failure (CHF), ACS, PE, and pneumonia are just some of the differential possibilities. Although a clinical exam and/or chest X-ray often makes the diagnosis more apparent, the cause of the complaint can be more elusive. In these cases, BNP assays, such as the Triage BNP Test (Biosite Inc., San Diego), can be helpful.

A neurohormone, BNP is secreted in conditions that cause volume or pressure overload of the ventricles. Studies have shown that at a cutoff point of 100 pg/mL, this marker was more accurate than either the National Health and Nutrition Examination Survey or Framingham criteria in differentiating CHF from non-heart failure disease as the cause of dyspnea. Other studies performed in EDs and urgent care settings have found that BNP can more accurately diagnose the cause of dyspnea than the patient history, physician exam, or laboratory test results. (24)

No perfect marker

The underlying truth of cardiac diagnosis is that because of the complexity of diagnosing cardiac disease, there is no such thing as the perfect marker. Although troponin comes closest to being ideal, it, too, must yield to other markers in some circumstances. For example, once it is released into the blood, troponin remains elevated for seven to 10 days. That makes it impractical for detecting new re-infarction that occurs during this period. In this situation, CK-MB or myoglobin are the better choices because they subside much faster after a cardiac event.

Common sense should also come into play in cardiac cases. If the patient's clinical presentation is not consistent with ACS, the physician should look for other cardiac--as well as noncardiac--conditions that could cause an elevation in these markers.

The laboratorian's contribution to cardiac patient evaluation

Physicians depend on laboratorians to provide fast, accurate test results. In addition to providing a comprehensive cardiac marker menu that delivers accurate results, labs today can help meet physician expectations, as well as improve operating efficiency, with just a few simple acts. For example, many labs are consolidating various testing functions in a single physical space and automating tasks to create faster, more accurate lab results. At my institution, automated instruments have taken over many of the lab's manual duties, freeing technologists to work more closely with physicians in interpreting patient test results. This helps improve TAT, leading to more timely and informed treatment decisions by physicians.

Good cardiac medicine also requires laboratorians and physicians to work together. Traditional turf boundaries have tended to segregate these professionals in different areas of the hospital, but the current environment demands that those fences be taken down.

Consider the complexities that both sets of professionals face when they try to interpret troponin test results. Troponin assays differ in their precision, specificity, and sensitivity, and are not standardized in other diagnostic dimensions. Thus, a blood sample run on one manufacturer's instrument may turn up a different result than one tested with another maker's assay.

Laboratorians understand the distinctions between assays and can help physicians sort through the confusion. By the same token, physicians are more knowledgeable about the human body's physiological processes and how to interpret a test result in light of a patient's individual history. They also may be better equipped to interpret a troponin result in the context of other cardiac testing, such as an ECG or BNP. Clearly, the best possible scenario is that the physician and laboratorian consult with each other on the proper evaluation of a troponin or other important test result.

Beyond the interpretation of individual results, physicians and laboratorians should be educating each other on an ongoing basis. The better they understand each other, the more efficiently they can work together in a crunch. This can make a crucial difference for patients in critical condition. Education can take place via formal meetings, memos, phone calls, and so on. What is important is not how it occurs but that it does occur in some fashion.

The right marker for the job, maximizing lab efficiency, and collaboration between physicians and laboratorians--this is a potent combination for improving cardiac care. Considering what is at stake, no healthcare institution or professional should settle for less.


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24. Christenson RH, Duh SH. Evidence-based approach to Practice Guides and Decision Tresholds for Cardiovascular Markers. Scand J Clin Lab Invest. 1999;59(suppl 230):90-102.

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Djiby Diop, MD, MMS, MPH is assistant professor of Emergency Medicine, director of Quality Assurance, and director of Master of Public Health at University of Massachusetts Medical Center, Worcester, MA.

By Djiby Diop, MD, MMS, MPH
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Title Annotation:Clinical Issues
Author:Diop, Djiby
Publication:Medical Laboratory Observer
Geographic Code:1USA
Date:Jan 1, 2004
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