Author + information
- †Department of Laboratory Medicine, University of California, San Francisco, California
- ‡Department of Medicine, University of California, San Francisco, California
- §Department of Emergency Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- ↵∗Reprint requests and correspondence:
Dr. Alan H. B. Wu, Department of Laboratory Medicine, San Francisco General Hospital, 1001 Potrero Avenue, Room 2M27, San Francisco, California 94110.
The origin of cardiac markers can be traced back to the mid-1950s with the finding that aspartate aminotransferase was useful in the detection of acute myocardial infarction (AMI) (1). Since then, there has been a steady stream of improvements of laboratory tests that aid in the diagnosis of AMI in terms of the discovery of new markers and analytic refinements of assays used to measure them. Aspartate aminotransferase as a cardiac marker was pushed aside by creatine kinase (CK) and CK-MB (2), which continue to be available in many hospitals today but are slowly being phased out in favor of cardiac troponin. The first troponin assays were cleared by the U.S. Food and Administration in 1994, but the “troponin era” can be traced to the redefinition of AMI by a joint committee of European and American cardiologists (3). Troponin was identified as the preferred serologic biomarker for acute coronary syndrome (ACS). Over the next dozen years, troponin assays have improved with respect to analytic sensitivity, assay reproducibility, freedom from interferences, and availability of point-of-care testing platforms. In addition, there has been an evolution of strategies that define the optimum cutoff concentrations. These assay modifications have led to further refinements in the guidelines in 2007 (4) and again in 2012 (5).
With each generation of troponin assays has come the reduction of upper limit of normal and cutoff concentrations. Cutoffs were initially set to separate those with AMI from those with unstable angina. When it became clear that patients with a mild increase in troponin in the context of unstable angina were at risk for future adverse cardiac events, the cutoffs were lowered to the 99th percentile of a healthy population. The first-generation assays were insufficiently sensitive to detect troponin in the sera of health subjects. Therefore, the 99th percentile limit was set at the assay's limit of detection, for example, 0.50 ng/ml. With current-generation high-sensitivity assays, the majority of healthy subjects have measurable troponin concentrations (i.e., above the limit of detection). This has further reduced the upper limit of normal to ≤0.010 ng/ml with the highest sensitive troponin assay currently available (6).
The implementation of improved troponin assays and the lowering of the 99th percentile have resulted in considerable confusion among emergency department (ED) physicians and cardiologists. Unlike CK-MB, for which cutoff concentrations were established to separate unstable angina from AMI, the use of the 99th percentile has resulted in detecting many more cases of increased troponin that are caused by a nonischemic origin. If one considers that troponin is a marker of myocardial injury, then these high results are not false indications of AMI but are true positives resulting from myocardial damage. Positive results are seen in patients with renal failure, heart failure, venous thrombosis, and many other diseases (7). The key in separating ischemic and nonischemic causes in patients with increased troponin is serial testing. The demonstration of a significant increase (or decrease) in troponin is indicative of an acute disease process, as opposed to an unchanging troponin result that is seen in chronic disease states.
Advancement in biomarker technology and the concomitant requirement to redefine safe clinical thresholds parallel the history of progress in other essential testing procedures in cardiology. Echocardiography, which like troponin assays is safe, relatively inexpensive, and readily available in EDs and primary care settings, is an example. As echocardiographic transducer and system technology have advanced, the range of disorders that it can detect and the accuracy of those diagnoses have increased with the quality of the images. With each significant jump in image quality, however, a repetitive pattern occurs: With improvements in sensitivity, details that were previously obscured may become apparent. Until the diagnostic bar is reset, normal findings may be misinterpreted as pathological. As a result, on a regular and recurring basis the entire spectrum of ultrasound-interpreting physicians must go through a new learning curve to accommodate the changes in the data quality. In some cases, the diagnoses most affected are those with great clinical impact, just as ACS is for troponin assays. In the case of echocardiography, recent improvements in near-field resolution with transthoracic echocardiographic imaging have been accompanied by an increase in clinical uncertainty regarding the right ventricular anterior wall, which was previously difficult to see in such detail. Because right ventricular dysplasia is a risk for arrhythmias and sudden cardiac death, uncertainty about what comprises “normal” right ventricular anatomy may lead to additional testing and clinical concerns for the provider and patient. With this issue, just as with prior episodes of data-quality resets, time and accumulation of experience will likely restore the impaired specificity of the test that follows these quantum leaps in imaging sensitivity as users become recalibrated to its use.
In this issue of the Journal, Cullen et al. (8) used a high-sensitivity troponin I assay with a cutoff of 26.2 ng/l. This assay is not yet cleared by the Food and Drug Administration, but it is available in Europe and Asia. They showed that in patients with a Thrombolysis In Myocardial Infarction risk score of ≤1 (i.e., low risk), the clinical sensitivity and negative predictive value for AMI were 99.2% and 99.7% respectively, when blood was sampled at the time of ED admission and 2 h thereafter (8). In the Online Appendix 6 of the article by Cullen et al.(8), the three missed patients are described in more detail. One (Patient #3) or maybe two patients (add Patient #1) did not meet many experts' criteria for a change in troponin, meaning that although they might have myocardial injury, it was not due to an AMI. With the exclusion of those patients, the negative predictive value would increase to 99.9%. These authors suggested that approximately 40% of patients admitted with suspected ACS can be safely discharged with a minimal risk for returning within 30 days with a major adverse cardiac event. Can high-sensitivity troponin assays be used to “rule out” ACS and facilitate early discharge?
From the ED perspective, chest pain is the second most common symptom and the leading cost of malpractice dollars spent. The historically conservative approach to avoid missing anyone with a potential ACS has led clinicians to admit many more patients than are subsequently found to have disease. This further affects ED crowding and boarding, which are associated with adverse outcomes for both patients with and without ACS (9). High-sensitivity troponin assays now allow us to detect this marker in some asymptomatic subjects without an acute medical symptom. By definition, a high-sensitivity assay can detect troponin in normal volunteers. When used in the ED setting, an “increased” or measurable high-sensitivity troponin value does not mean that the patient has ACS or even that admission is warranted. Many groups are currently trying to determine when a positive troponin is not due to ACS and how best to manage these patients.
It still remains to be demonstrated prospectively that patients discharged early from the ED have longer-term safety comparable to those receiving more conventional screening. Both early and conventional discharge strategies often rely on additional diagnostic evaluation with stress testing or at follow-up outpatient visits. This type of evaluation will continue to be required to answer the “if not cardiac in etiology, then what?” question that must always accompany any episode of chest pain. Abnormal high-sensitivity troponin values, even if the trend does not suggest acute ischemia, may underscore the importance of such follow-up testing and targeted attention from primary care providers.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Wu receives honoraria from Abbott, and is a consultant for Singulex. Dr. Bolger has reported that she has no relationships relevant to the contents of this paper to disclose. Dr. Hollander receives research funding from Alere, Siemens, Brahms, and Abbott; and is a consultant to Radiometer and Janssen.
- 2013 American College of Cardiology Foundation
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