EDITORIAL COMMENT
Highly Sensitive TroponinsThe Answer or Just More Questions?*
Judd E. Hollander, MD*
Department of Emergency Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
* Reprint requests and correspondence: Dr. Judd E. Hollander, Department of Emergency Medicine, Ground Floor, Ravdin Building, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104-4283 (Email: hollandj{at}uphs.upenn.edu).
Key Words: troponin I • unstable angina • myocardial infarction
In 2006, the Institute of Medicine released a report detailing the crisis in emergency care (1). Our current approach to the care of patients with potential acute coronary syndromes (ACS) has contributed to this crisis. Physicians admit the majority of the 6 million patients that present to the emergency department (ED) with signs and symptoms of a possible ACS (2), yet a relatively small percentage actually turn out to have a cardiac etiology for their chest pain. The consequences of this practice have resulted in expenses exceeding $8 to $10 billion annually to rule out acute myocardial infarction (AMI) and ACS (3,4). Nonetheless, it should be noted that there are more negative consequences than simply cost. As ED patient volumes have grown disproportionately to inpatient bed availability, boarding of admitted patients has become commonplace (1,2). Patients with chest pain syndromes are the most common cohort of patients boarding in the ED awaiting admission (3). Emergency department crowding has recently been proven to have an adverse impact on important patient-oriented outcomes across a broad spectrum of diseases (5–8). In particular, patients with ACS have an increased risk of short-term adverse outcomes when they present to the ED during more crowded times (7). Thus, it is more important than ever to be able to distinguish patients with ACS from those with a noncardiac etiology early in the evaluation.
Decades of well-thought-out clinical studies have provided a wealth of information regarding risk of AMI and adverse cardiovascular outcomes. Risk stratification tools, such as the Goldman rule, ACI-TIPI (Acute Cardiac Ischemia-Time Insensitive Predictive Instrument), and Thrombolysis In Myocardial Infarction risk score distinguish high-risk from low-risk patients (9–11). Unfortunately, they do not allow physicians to reliably identify patients who are safe for discharge from the ED without serial cardiac markers or provocative testing.
Historically speaking, the initial plasma sample of a cardiac marker detected no better than 30% to 40% of patients with non–ST-segment elevation myocardial infarction (NSTEMI) (9). They have not been able to detect unstable angina. Efforts to enhance the utility of cardiac markers to rapidly identify higher-risk patients with ACS as well as to enable the expeditious discharge of patients without disease have focused on several approaches: more frequent serial sampling (12), combinations of markers based on release kinetics (13,14), and combinations of cardiac markers based on the pathophysiology of AMI (15,16).
Although troponin and creatine kinase (CK)-MB have approximately the same rate of increase, when used together at the time of ED presentation diagnostic sensitivity increases more than 25% (17). A combination of myoglobin and CK-MB has a sensitivity of 85% at the time of presentation. It attains a 100% sensitivity, specificity, and negative predictive value within 4 h of ED presentation (14). Combinations of myoglobin and troponin I can achieve a diagnostic sensitivity of 97% with a 99% negative predictive value, within 90 min of ED presentation (12). Although combination strategies enhance sensitivity, they seem to do so at the cost of specificity. They also do not obviate the need for provocative testing or identify patients with unstable angina, and therefore have not been shown to help reduce the admission rate for patients ultimately found to be disease free.
Although population-based studies of markers of inflammation and platelet activation have found a relationship between marker elevations and long-term prognosis, similar results have not been found in the acute setting. Markers of platelet activation such as P-selectin are theoretically attractive because they can detect platelet activation before myocardial injury; however, they do not identify patients with AMI any better than CK-MB (15). The utility of inflammatory markers in longitudinal cohort studies do not seem to apply to patients in the ED, where most patients with potential ACS have confounding medical conditions that increase the likelihood of abnormal values. Similarly, when added to markers of cell death, B-type natriuretic peptide (BNP), which is secreted from the ventricles in response to pressure or volume overload, increases sensitivity for detection of patients with adverse cardiovascular outcomes, but at the cost of decreased specificity (16).
Sometimes the answer to our wishes lies right beneath the surface. The data reported by Venge et al. (18), in this issue of the Journal, suggest that we might not need new markers, we may just need better assays. Venge et al. (18) used a highly sensitive assay and found normal values of troponin in a cohort of healthy asymptomatic patients. Using an upper limit of normal derived from these healthy patients and comparing it to values from the GUSTO-IV (Global Utilization of Strategies To open Occluded arteries IV) trial cohort, they found a sensitivity of 85% and a specificity of 90% for death or MI. Wilson et al. (19) examined 50 NSTEMI patients with an initially negative troponin by conventional assay using a nano-troponin I assay (99th percentile of  0.002 ng/ml) and found that 100% had detectable levels within 2 h. In a similar evaluation of unstable angina patients with documented negative troponin values out to 24 h, 90% had detectable values using the nano-troponin I (19). Our group has examined 10 patients with NSTEMI who had undetectable troponin values on the initial sample using an older-generation troponin assay (upper reference limit, 600 pg/ml). Samples from these patients at presentation, 90 min, and 180 min were measured by a highly sensitive assay (upper reference limit 2.8 pg/ml). All 10 were >35 pg/ml on the highly sensitive assay at presentation (20). Thus, it seems highly likely that these highly sensitive troponin assays will allow us to detect many NSTEMI patients earlier than current-generation assays. It may even enable the objective identification of patients with unstable angina.
Ideally, a marker with a high sensitivity and high negative predictive value is useful to allow expeditious evaluation and discharge from the ED. Markers with high specificity and positive predictive values are ideal to tailor care for patients at high risk of cardiovascular complications. Both are needed to provide optimal management to all patients who present to the ED with potential ACS. Although none of us possesses a magic crystal ball, it seems reasonable to pre-suppose that as with every other incremental improvement, we will trade specificity for sensitivity. As the analytical ability to measure troponin continues to move lower, we will be forced to readjust our approach to patient management. Assume that for every 100 patients presenting to the ED with symptoms possibly consistent with ACS, 65 are admitted to the hospital (5 to the cardiac care unit, 10 to cardiology, and 50 to internists or hospitalists). At the end of the hospitalization, 15 are diagnosed with ACS, 50 with noncardiac etiologies of their symptoms. Now imagine that a highly sensitive troponin assay can achieve 94% sensitivity on the initial sample, but will have only 80% specificity. This new assay could reduce the admission rate from 65 patients to 31, enabling the discharge of 69 patients (nearly doubling the discharge rate from 35) while maintaining a miss rate of about 1%. From the ED perspective, it would help reduce overcrowding, thereby benefiting the larger subset of ED patients who may be subjected to harm from long waits to be evaluated and treated. From the perspective of the internist or hospitalist, it would result in fewer admissions of patients without disease. However, it is possible that all 31 troponin-positive patients (of whom only 14 actually had disease) would be admitted to the cardiology service, greatly increasing the percentage of possible ACS patients without disease to more than 50%. It might soon become time for the cardiologist, emergency physician, and primary care provider to re-evaluate current diagnostic and disposition pathways to maximize patient outcomes. Future research will need to determine not only the diagnostic and prognostic characteristics of these assays, but also the best way to translate their use into clinical practice. We will need to define the approach to management of this new class of troponin-positive patients. They may or may not benefit from the usual cadre of our evidence-based treatments.
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Footnotes
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Dr. Hollander received research funding from Biosite and Nanosphere.
* 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. 
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References
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1. Institute of Medicine Hospital-Based Emergency Care: At the Breaking Point. 2006 http://www.nap.edu/catalog/11621.html#tocAccessed May 12, 2009.2. Pitts SR, Niska RW, Xu J, Burt CW. National Hospital Ambulatory Medical Care Survey: 2006 emergency department summary. National Health Statistics Reports; No. 7. Hyattsville, MD: National Center for Health Statistics; 2008. 3. Bayley MD, Schwartz JS, Shofer FS, et al. The financial burden of emergency department congestion and hospital crowding for chest pain patients awaiting admission Ann Emerg Med 2005;45:110-117.[CrossRef][Web of Science][Medline] 4. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnosis of acute cardiac ischemia in the emergency department N Engl J Med 2000;342:1163-1170.[CrossRef][Web of Science][Medline] 5. Chalfin DB, Trzeciak S, Likourezos A, et al. Impact of delayed transfer of critically ill patients from the emergency department to the intensive care unit Crit Care Med 2007;35:1477-1483.[CrossRef][Web of Science][Medline] 6. Carr BG, Kaye AJ, Wiebe DJ, et al. Emergency department length of stay: a major risk factor for pneumonia in intubated blunt trauma patients J Trauma 2007;63:9-12.[CrossRef][Web of Science][Medline] 7. Pines JM, Pollack Jr. CV, Diercks DB, Chang AM, Shofer FS, Hollander JE. The association between emergency department crowding and adverse cardiovascular outcomes in patients with chest pain Acad Emerg Med 2009 Jun 22[E-pub ahead of print]. 8. Hollander JE, Pines JM. The emergency department crowding paradox: the longer you stay, the less care you get Ann Emerg Med 2007;50:497-499.[CrossRef][Web of Science][Medline] 9. Selker HP, Zalenski RJ, Antman EM, et al. An evaluation of technologies for identification of acute cardiac ischemia in the emergency department: a report form a National Heart Attack Alert Program Working Group Ann Emerg Med 1997;29:13-87.[CrossRef][Web of Science][Medline] 10. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making JAMA 2000;284:835-842.[Abstract/Free Full Text] 11. Chase M, Robey JL, Zogby KE, Sease KL, Shofer FS, Hollander JE. Prospective validation of the TIMI risk score in the emergency department chest pain patient population Ann Emerg Med 2006;48:252-259.[CrossRef][Web of Science][Medline] 12. McCord J, Nowak RM, McCullough PA, et al. Ninety-minute exclusion of acute myocardial infarction by use of quantitative point-of-care testing of myoglobin and troponin I Circulation 2001;104:1483-1488.[Abstract/Free Full Text] 13. Newby LK, Storrow AB, Gibler WB, et al. Bedside multimarker testing for risk stratification in chest pain units: the chest pain evaluation by creatine kinase-MB, myoglobin, and troponin I (CHECKMATE) study Circulation 2001;103:1832-1837.[Abstract/Free Full Text] 14. Kontos MC, Anderson FP, Hanbury CM, et al. Use of the combination of myoglobin and CKMB mass for the rapid diagnosis of acute myocardial infarction Am J Emerg Med 1997;15:14-19.[CrossRef][Web of Science][Medline] 15. Hollander JE, Muttreja MR, Dalesandro MR, Shofer FS. Risk stratification of ED patients with acute coronary syndromes using P-selectin J Am Coll Cardiol 1999;34:95-105.[Abstract/Free Full Text] 16. Brown AM, Sease KL, Robey JL, Shofer FS, Hollander JE. The impact of BNP in addition to troponin I, CK-MB, and myoglobin on the risk stratification of ED chest pain patients with potential ACS Ann Emerg Med 2007;49:153-163.[CrossRef][Web of Science][Medline] 17. Green GB, Beaudreau RW, Chan DW, DeLong D, Kelley CA, Kelen GD. Use of troponin T and creatine kinase MB subunit levels for risk stratification of emergency department patients with possible myocardial ischemia Ann Emerg Med 1998;31:19-29.[CrossRef][Web of Science][Medline] 18. Venge P, Johnston N, Lindahl B, James S. Normal plasma levels of cardiac troponin I measured by the high-sensitivity cardiac troponin I access prototype assay and the impact on the diagnosis of myocardial ischemia J Am Coll Cardiol 2009;54:1165-1172.[Abstract/Free Full Text] 19. Wilson SR, Sabatine MS, Braunwald E, Sloan S, Murphy SA, Morrow DA. Detection of myocardial injury in patients with unstable angina using a novel nanoparticle cardiac troponin I assay: observations from the PROTECT-TIMI 30 trial Am Heart J 2009;158:386-391.[CrossRef][Medline] 20. Apple FS, Murakami MA, Hollander JE, Shipp GW. Preliminary performance of a high sensitive gold nanoparticle-based cardiac troponin I assay: proof of concept study of the Nanosphere Verigene System (letter) Clin Chem 2009In press.
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