Ruptured Plaques and Leaking Cells: Cost-Effectiveness in the Diagnosis of Acute Coronary Syndromes

Acute coronary syndromes arise when an atherosclerotic plaque becomes unstable. The cap develops either superficial erosions with overlying thrombus or, more commonly, deep fissures that cause the plaque to swell with clotted blood and encroach on the arterial lumen. Plaques become unstable when the fibrous matrix surrounding the lipid core is attenuated by the action of cytokines from T lymphocytes, which inhibit the synthesis of the matrix, and by metalloproteinases from activated macrophages, which degrade the matrix. The cause of the initial surface breach of the weakened cap may be chemical, caused by reactive oxygen species, or mechanical, caused by focal stresses. The consequent growing fault may reach the plaque center; the resulting acute eruption of the lipid core amplifies local thrombosis. Abrupt occlusion of an artery unprotected by recruitable collaterals leads to acute regional ischemia. Complete and persistent occlusion produces myocardial infarction. Partial occlusion or occlusion that waxes and wanes results in unstable angina. Plaques can be multiple or single, regress, develop recurrent instability, or remain dormant for years (1-3). Study of the unstable plaque thus resembles volcanology and plate tectonics; the detection of clinical and biological markers of plaque instability, ischemia, and infarction is like seismography. The most important early clinical markers of ischemic events are chest pain and abnormalities in electrocardiographic repolarization. Their significance has been validated repeatedly, and they parallel development of regional hypokinesis and release of lactate and nucleosides (4). Cell necrosis follows total occlusion and is marked by liberation of cytoplasmic enzymes, such as creatine kinase (CK)-MB (the predominant cardiac isoform of CK), and structural components, such as troponin I. When patients present to the emergency department with the classic clinical markers of myocardial infarction, clinicians have little difficulty making the diagnosis. However, such patients constitute fewer than 14% of those who come to the emergency department because of acute chest pain (5). The problem, therefore, is to separate the 35% of patients with unstable angina from the 50% or more whose pain is not of ischemic origin (5). The burgeoning use of new markers of myocardial necrosis, in turn, has raised questions about cost-effectiveness, especially relating to possible redundancy in routine simultaneous measurement of CK-MB and troponin I (6, 7). The two substances differ in their intracellular locations, molecular size, and dynamics of their liberation after cell death. Creatine kinase-MB is a cytoplasmic enzyme with a molecular weight of 86 000. The high concentration of CK-MB in the myocardial cell reflects the importance of CK in catalyzing transfer of the phosphate of adenosine triphosphate to creatine and then to adenosine diphosphate in a storage-and-shuttle operation. Troponin I (molecular weight of 23 500) is the inhibitory component of the three-part sarcomeric troponin complex, which binds cyclically to tropomyosin and thereby regulates the interaction between actin and myosin (8). Creatine kinase-MB appears in the blood after 2 to 5 hours of cell necrosis; levels of this substance decrease to normal after 2 to 3 days. Troponin I appears slightly later, and levels can remain elevated for 10 to 12 days (7). Increases in serum levels of either substance are very precise in detecting infarction and can reflect its size. Creatine kinase-MB can be liberated after skeletal muscle injury from trauma or surgery, whereas troponin I probably remains more specific for cardiac injury (7). Precise and rapid diagnosis of ischemia and infarction is crucial, given that prompt treatment with thrombolytics, heparin, and antiplatelet agents and intervention with angioplasty and stenting can salvage jeopardized myocardium and reduce morbidity and mortality rates. Public awareness of this fact has increased emergency department visits for chest pain in the United States to more than 5 million per year (9). This has fostered a proliferation of studies on the predictive accuracy of clinical and laboratory markers of myocardial ischemia and necrosis. Emphasis has been on precise diagnosis to avoid both unnecessary admissions and, more important, discharges of patients with missed diagnoses of acute coronary syndromes; in the latter group, the subsequent death rate from missed events may be twice that of patients who are admitted (5). Polanczyk and colleagues (10), whose report appears in this issue, used CK-MB and troponin I to formulate triage strategies for acute chest pain in the emergency department and subjected these strategies to a cost-effectiveness analysis. They used a database that was described in earlier studies to obtain information on more than 1000 patients with chest pain (5, 11, 12). These previous reports and those of others (13) have established the prevailing algorithm for diagnosis: Initial, pretest risk categories are well defined by the clinical and electrocardiographic presentations. If the CK-MB level is elevated, the diagnosis of infarction is established. If the electrocardiographic changes are uncertain and the CK-MB level is normal, an elevated troponin I level improves predictive accuracy for infarction; however, a normal troponin I level does not exclude subsequent cardiac events. When levels of both serum markers remain normal, exercise testing, if feasible, contributes significantly to diagnosis. Polanczyk and colleagues (10) examined seven diagnostic options for all patients presenting to the emergency department with chest pain: exercise testing, measurement of CK-MB alone, measurement of CK-MB followed by measurement of troponin I if the CK-MB level is normal, measurement of CK-MB followed by troponin I measurement only if the CK-level MB is normal and electrocardiography indicates ischemia, measurement of both CK-MB and troponin I, measurement of troponin I alone, and hospitalization without measuring serum markers. The outcome and cost for each branch in the decision tree were then estimated and compared by using incremental cost-effectiveness analysis. The analysis was also stratified by patient age and risk category. In this method of analysis, when a particular strategy is found to produce an outcome equal to or better than that provided by the preceding base test and also costs less, it is called dominant. However, some expensive technologies may be so highly effective that they are cost-effective (14). An important example of this in the triage of chest pain in the emergency department is the use of transesophageal echocardiography or magnetic resonance imaging for the diagnosis of suspected aortic dissection. What were the results of this analysis, and did they modify the prevailing algorithm? The reader must be cautioned against misconstruing as clinically appropriate the authors' benchmark hypothetical constructs of immediate hospitalization or exercise testing. These two branches of the tree are included only as the extremes of the model for analysis of cost-effectiveness. The final analysis revealed that measurement of CK-MB alone was a reasonable, cost-effective strategy if a patient was a candidate for early stress testing. If the CK-MB level was normal, troponin I measurement as a second test was most cost-effective in patients older than 65 years of age and in those with electrocardiographic evidence of ischemia. In patients with a high probability of infarction (50% or more), the best strategy was immediate hospitalization, a significant change from the prevailing paradigm. Routine use of both CK-MB and troponin I measurement was not cost-effective. Cost-effectiveness analyses depend on the validity of the assumptions used to generate the base case. In addition to the uncertainty generated by these assumptions, Polanczyk and colleagues admit that the use of CK-MB as the basis for diagnosing myocardial infarction in this study may weaken its derived value in the diagnostic hierarchy. Furthermore, from a macroeconomic perspective, it is certainly not desirable to use CK-MB and troponin I measurement inappropriately, but it is difficult for most clinicians to marshal great concern about added cost from serial or tandem use of these two excellent markers of myocardial necrosis when each test costs less than $15.00. For clinicians faced with caring for individual patients with uniquely complex illnesses, the most reassuring conclusion from this study with a societal perspective was that no single strategy for use of CK-MB and troponin I was best for all patients. It should be remembered that in some patients with unstable angina, chest pain and ischemic changes seen on electrocardiography can decrease or disappear spontaneously as flow improves, an obstructing plaque shrinks, a thrombus lyses, or vasospasm subsides. The lack of significant elevations in CK-MB and troponin I levels means only that necrosis was absent or minimal. Finally, exercise stress tests may have negative results if a plaque shrinks to occupy less than 50% of the coronary lumen. The incidence of subsequent acute ischemic events may be small but catastrophic; in patients at moderate to high risk, we believe that coronary angiography is advisable. In the future, new technologies will certainly make early diagnosis more precise. Noninvasive evaluation of coronary arterial lumens by magnetic resonance angiography could become sufficiently validated, inexpensive, and available to modify current diagnostic algorithms (15). Similarly, serum markers of continued plaque instability, such as P-selectins or other indicators of inflammation or even plaque imaging, may alter the management of patients with unstable angina. Algorithms are useful to guarantee that strategies in managing patients with specific illnesses are based on evidence and are complete, but their rigid application c