Cardiac markers: Cost-effective triage for MI admission and therapy

For more than 30 years, the diagnosis of acute myocardial infarction (AMI) was based on criteria established by the World Health Organization (WHO) and predicated on finding two of three sentinel events: positive clinical history, including the presence of chest pain; unequivocal electrocardiographic (ECG) changes; and a rise and fall in the activities of enzymes in serum collected over the appropriate intervals in time.¹ Under this definition, a patient could suffer AMI without demonstrating a change in cardiac marker levels. 

In the year 2000, a joint effort between the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) redefined the criteria for diagnosis of AMI. Under the new definition, an AMI patient must have either pathologic findings at autopsy, or a rise and fall in biochemical markers in the context of coronary artery ischemia (i.e., clinical symptoms, ECG changes, or need for angioplasty).² The development and characterization of cardiac troponin as a very specific and sensitive marker for myocardial damage, and the widespread implementation of this test within clinical laboratories, were the motivating factors for this revision. Full acceptance of this redefinition will lead to substantially higher numbers of AMIs, as patients who previously had unstable angina and a mild increase in cardiac troponin will now be diagnosed as having an AMI. Figure 1 illustrates the annual incidence of cardiovascular disease in the U.S., and the impact of the new definition for patients presenting to the emergency department (ED) with chest pain.³

Important remaining questions for clinical laboratory managers and administrators are, which markers should be tested, what is the frequency of blood collections, what is the required turnaround time (TAT) for cardiac marker assay results, and what is the role of point-of-care testing devices? In order to answer these important questions, it is necessary to know how patients with chest pain are currently triaged from the emergency departments, and how results of lab tests impact the therapeutic management decisions for patients with acute coronary artery disease. In order to meet new demands and needs, it is equally important to factor in the capabilities of the clinical laboratory with regard to resources, equipment, and priorities.

Chest pain units (CPUs)

A major innovation among EDs today is the development and implementation of chest pain units. The primary objective of CPUs is to rapidly rule out or rule in myocardial disease for patients who present with chest pain. Those who are ruled out for acute cardiac disease should be evaluated for other causes of pain and admitted to the appropriate level of care, or discharged to home. Those who are ruled in should be immediately treated and transferred to the coronary care unit. ED physicians must assess the likelihood of acute coronary disease for each chest pain patient, and balance the high costs of unnecessary admissions against the real possibility of misdiagnosis of AMI or impending cardiac risk. A liberal admission policy will result in exposure of patients to unnecessary therapies and nosocomial infections. A liberal discharge policy will result in an increase in the number of missed AMI diagnoses, currently the leading cause of malpractice lawsuits in the U.S. Given these undesirable outcomes, the objectives for establishing chest pain units are to improve the efficiency and effectiveness in the clinical management of chest pain patients, and to reduce total operating costs. The attractiveness of chest pain units is that they can simultaneously lower both the number of unnecessary admissions and lawsuits due to wrongful discharges.

There are two critical elements to the success of chest pain units. First is the rapid rule-out of acute myocardial infarction. This can be accomplished by use of continuous ECG monitoring and serum cardiac marker testing using a frequent specimen collection and testing protocol.
Figure 2 compares the conventional conservative rule-out strategy for chest pain patients versus the aggressive approach used for CPUs. These protocols are not used for those who present with ST-segment elevations or Q waves on the ECG, as these patients have AMI and should be immediately treated with thrombolytics or angioplasty and admitted. Patients with an equivocal ECG should be further evaluated for the presence or absence of cardiac disease. Biochemical markers such as myoglobin, creatine kinase and the MB isoenzyme, and cardiac troponins (T or I) can reliably rule out AMI if blood is collected at the appropriate interval after onset. Most CPU protocols measure biomarkers at presentation and at six to nine hours thereafter. Negative results on at least two specimens collected during this interval effectively rule out AMI. 

The second element of successful CPUs is the proper and rapid assessment of future short-term cardiovascular risk (four to six weeks). A patient who is ruled out for AMI might still have active coronary disease and suffer a cardiac event in the near future. Thus patients with negative ECGs and cardiac markers should be further evaluated by a stress test, e.g., an exercise treadmill or nuclear perfusion imaging. These tests can detect the presence of myocardial ischemia (low oxygen delivery to the heart) under controlled laboratory conditions. Patients who are positive for ischemia are at high risk for spontaneous events and should be aggressively managed with drug therapy or cardiac catheterization.

There are several variations that different emergency departments have used with regard to the timing of blood samples and the number of cardiac markers tested. While most CPUs wait for at least six hours before a triage decision is made, some centers have produced good results using a 90-minute rule-out protocol. Ng et al. reported 100 percent sensitivity and negative predictive value on 1,285 consecutive patients presenting to a Veterans Affairs Medical Center.⁴ McCord et al. reported similar findings on 817 consecutive ED patients.⁵ These data would appear to be in conflict with the known release pattern of cardiac markers that have shown that these proteins do not increase in blood for three to six hours after the onset of damage myocardial damage.⁶ Because the 90-minute rule-out protocol refers to time of presentation and not onset, it is likely that in the majority of these patients, the actual onset of AMI had occurred several hours (three to six) before the patient presented to these medical centers. AMI patients who present within one hour of onset will likely require a longer duration of observation than 90 minutes before cardiac disease can be ruled out.

In terms of the optimum number of biomarkers that should be used for chest pain patients, the National Academy of Clinical Biochemistry (NACB) and the International Federation of Clinical Chemistry (IFCC) recommend two markers: one that detects AMI early (e.g., myoglobin or CK-MB isoforms) and one that is definitive (e.g., cardiac troponin T or I, or CK-MB mass).^7,8 These groups suggested that cardiac troponin is superior to CK-MB for the definitive diagnosis and AMI and suggest a gradual phase out of the enzyme test. However, in the CHECKMATE study, three markers (myoglobin, CK-MB mass and troponin I) were used in a multicenter chest pain evaluation study.⁹ Using 30-day outcomes of death and myocardial infarction, they found that the three-marker strategy was superior to use of either one marker, or the combination of CK-MB and troponin I. However, risk stratification was not compared against using the specific combination of an early and definitive marker (myoglobin and troponin I). It should be noted that in some states, reimbursement is not permitted for a three-biomarker strategy, which may limit some laboratories in using the three-marker approach.

Rationale for rapid TATs for cardiac markers

To obtain maximum efficiency, hospitals that have engaged in an accelerated protocol for the triaging of patients who present with chest pain must have the availability of receiving stat cardiac marker results. Additional ED expenses are expected if the labs TAT is sufficiently slow that it results in delays in making triaging decisions. It might also limit the number of beds available to the unit at any given time. Patient satisfaction is another issue that should be considered. Patients who are ruled out for acute coronary syndromes and their attending physicians will appreciate a quick discharge, assuming the decision made is the correct one. 

There may also be medical benefits in terms of morbidity and mortality for early detection of acute coronary syndrome. Clinical studies have shown that patients with unstable angina and increased concentrations of cardiac troponin have reduced incidence of cardiac death and recurrent AMI when given anti-thrombotic (e.g., low molecular weight heparin) and anti-ischemic (e.g., glycoprotein IIb/IIIa inhibitors) therapies relative to unstable angina patients with a normal troponin.^10,11 These and other clinical trials have led to the recommendation made by a joint committee of the ACC and the American Heart Association (AHA) that these drugs be used on patients with unstable angina and non-ST segment elevation AMI.¹² Intuitively, it would appear that early administration of these thrombin and platelet inhibitors (i.e., within a few hours of diagnosis) would be more beneficial to patient outcomes than late treatment (e.g., next day or two). This would provide further rationale for rapid analysis for cardiac markers. Clinical studies have been published comparing early invasive vs. conservative strategies with regard to percutaneous coronary intervention (PCI).^13,14 Morrow et al. showed that testing for cardiac troponins (T or I) was effective in identifying those patients with acute coronary syndromes who benefit most from aggressive therapies, in terms of reduced incidence of adverse endpoints (deaths, AMI, and rehospitalization at six months).¹⁵ However, the time from diagnosis to PCI in these studies was not immediate (i.e., PCI conducted four hours to 48 hours after diagnosis). Therefore, the need for a turnaround of under one hour was not necessarily advocated in these studies.

Turnaround times

Given the new importance of cardiac markers in the diagnosis of myocardial infarction, there is new emphasis placed on the laboratory in reducing the turnaround time (TAT) for cardiac marker testing. The NACB and IFCC advocate a one-hour TAT for cardiac marker results.^7,8 This time limit was also recommended by the ACC/AHA,¹² although they further acknowledged that a 30-minute TAT was preferable. Missing in these recommendations was a precise and universally accepted definition of TATs. A laboratorian might define TAT from the receipt of the sample in the laboratory to the reporting of results by phone or computer only, as these steps are within the labs immediate control. An ED physician, however, might define the TAT from the time he writes the order in the medical record to the time a management decision is made on the basis of the test result. Despite these different preconceptions of turnaround time, resources should be allocated and process improvements should be made throughout the system to reduce
TATs. 

Dr. Wu is a member of the Department of Pathology and Laboratory Medicine at Hartford Hospital in Hartford, CT.

References

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