High-sensitivity troponin assays have the potential to offer clinicians across the United States novel diagnostics strategies in the assessment of patients with chest pain and should be widely available subject to FDA approval. High-sensitivity troponin assays have a coefficient of variation of 10% or less at the 99th percentile (the upper limit of the reference population) and are able to detect cardiac troponin in at least 50% of the reference population.¹ The high precision of these assays at very low concentrations, in comparison with contemporary assays, enables accurate quantification of troponin in most healthy people. Much of the recent focus within published literature has been on the use of high-sensitivity troponin assays in the identification of low-risk emergency department (ED) patients presenting with suspected cardiac chest pain who are at low risk of adverse cardiac events. These patients may be suitable for early discharge from the ED with outpatient follow-up. Such rapid rule-out strategies may serve to substantially reduce hospital admissions and have major benefits for healthcare providers.

Currently, rapid rule-out strategies may be broadly separated into two distinct categories. The first utilizes the ability of high-sensitivity troponin assays to measure low concentrations of troponin with cut-off values below the 99th percentile.^2-5 The second uses conventional cut-offs for high-sensitivity troponin assays in combination with chest pain risk scores.^6-8 Those protocols employing low cut-off values for high-sensitivity troponin have consistently demonstrated a high diagnostic accuracy for acute myocardial infarction.^2-5 However, by not including those patients who require urgent revascularization, this singular endpoint does not represent the full spectrum of clinically relevant acute coronary syndromes (ACS). Consequently, when urgent revascularization is added as an endpoint, the diagnostic performance of low-cut off values of high-sensitivity troponin diminishes to levels that may considerably limit clinical applicability.^7,9 Those low cut-off value diagnostic strategies that have been published also fail to incorporate important risk-stratification factors gathered by the physician from clinical evaluation. When included in chest pain risk scores, these clinical factors allow the clinician to estimate the risk of ACS even in the absence of high-sensitivity troponin elevations. It is therefore intuitive that the incorporation of chest pain risk scores with early high-sensitivity troponin testing may be a more acceptable option for clinicians.

In 2011, 27 chest pain risk scores were available for clinical use¹⁰ with considerable variation in their uptake.¹¹ Although this list has undoubtedly grown since then, the majority of risk scores have not been tested in combination with high-sensitivity troponin assays to identify those patients suitable for early discharge from the ED. Yet, where such combination strategies have been used, they have shown considerable promise. The modified 2-Hour Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker (ADAPT) protocol⁶ utilizes a combination of the Thrombolysis In Myocardial Infarction (TIMI) risk score together with 0- and 2-hour high-sensitivity troponin I results. In a multinational prospective observational development and validation cohort study,⁶ this method identified approximately 40% of low-risk patients who were potentially suitable for early discharge. In this study, the sensitivity and negative predictive value (NPV) for major adverse cardiac events was >99% when a TIMI score of ≤1 was used. Findings were similar when tested with a high-sensitivity troponin T assay.⁸ As a result, expert consensus guidelines have recently recommended the modified ADAPT protocol for clinical implementation.¹²

However, some issues remain. First, the use of the TIMI score, which was originally developed to predict mortality in patients with confirmed ACS, could be considered counterintuitive in a low-risk population. Risk scores specifically designed to be used in an ED population may improve the efficiency of identifying patients who may be suitable for early discharge. Second, the ADAPT protocol still requires serial high-sensitivity troponin testing over 2 hours, which may limit efficiency gains in comparison with a single blood draw rule-out strategy. To this end, recent exploratory work has compared the ability of five established risk scores (modified Goldman, TIMI, Global Registry of Acute Coronary Events, History, ECG, Age, Risk factors and Troponin [HEART], and the Vancouver Chest Pain Rule), used in combination with a single high-sensitivity troponin T or high-sensitivity troponin I result taken at presentation to the ED, to identify low-risk patients who may be suitable for early discharge.¹³ The study findings were encouraging: Two risk scores (TIMI 0 or ≤1 and modified Goldman) in combination with high-sensitivity troponin T and two risk scores (TIMI 0 and HEART ≤3) with high-sensitivity troponin I have the potential to achieve an NPV of >99.5% (and sensitivity >98%) for fatal/nonfatal acute myocardial infarction while identifying >30% of patients who are potentially suitable for early discharge. This diagnostic performance suggests future clinical applicability of a strategy that uses a risk score and single blood draw strategy may follow. However, this approach requires validating in a prospective multicenter study (ideally a randomized controlled trial) that examines safety and cost effectiveness across different risk scores and high-sensitivity troponin assays, with an endpoint that includes urgent revascularization. As yet, the optimum choice of risk score and assay combination remains unknown.

Recently, the HEART score has been supported for use in US populations on the basis of safety with serial contemporary troponin testing,^14,15 and efficiency gains.¹⁶ However, we urge caution when extrapolating these results into clinical use based on a single high-sensitivity troponin result. This is because the sensitivity for ACS of a HEART score ≤3 in conjunction with a single high-sensitivity troponin T result is only 93% (95% confidence interval, 85-98%) and has a similar diagnostic accuracy to the subjective clinical judgement of risk or gestalt.¹⁷

A key concept in the evaluation of diagnostic strategies examining early rule-out of ACS is the reporting and interpretation of diagnostic accuracy statistics, primarily sensitivity and NPV. The NPV is directly related to the prevalence of the target disease in the specific population under consideration and represents the post-test probability of a negative test. When considering clinical implementation of a diagnostic strategy, it is important to establish the NPV for each hospital so that an attending clinician can best interpret a negative test (i.e., how does the test perform in a given clinical population). NPV should therefore not be used to recommend generalization of a test across populations with varying disease prevalence. Sensitivity, on the other hand, is not affected by the disease prevalence and represents the true positive rate. This is more useful to clinicians in establishing the validity of a diagnostic test on an individual patient level. The primary marker of whether a rule-out strategy is ready for implementation in a clinical environment is safety, and this can only be truly gauged from the reporting of sensitivity. Despite this, recent studies published in high-impact journals have failed to openly report sensitivity,^2,4 and others have concluded that a rule-out strategy is safe based on an NPV of >99% but with sensitivities <98%.⁵ This is a concerning trend, and we recommend complete reporting of diagnostic-accuracy statistics in the future.

The combination of high-sensitivity troponin testing and chest pain risk scores have the potential to reduce the door-to-discharge time for low-risk patients with suspected cardiac chest pain. However, further work is needed to compare diagnostic strategies and identify the optimum risk-stratification strategy. This can be achieved through the use of randomized trials that report safety and health-economic outcomes and rationalize the use of downstream testing.

References

1. NICE diagnostics guidance [DG15]. Myocardial infarction (acute): Early rule out using high-sensitivity troponin tests (Elecsys Troponin T high-sensitive, ARCHITECT STAT High Sensitive Troponin-I and AccuTnI+3 assays) (National Institute for Health and Care Excellence website). 2014. Available at http://www.nice.org.uk/guidance/dg15. Accessed 10/02/2016.
2. Bandstein N, Ljung R, Johansson M, Holzmann MJ. Undetectable high-sensitivity cardiac troponin T level in the emergency department and risk of myocardial infarction. J Am Coll Cardiol 2014;63:2569-78.
3. Zhelev Z, Hyde C, Youngman E, et al. Diagnostic accuracy of single baseline measurement of Elecsys Troponin T high-sensitive assay for diagnosis of acute myocardial infarction in emergency department: systematic review and meta-analysis. BMJ 2015;350:h15.
4. Shah AS, Anand A, Sandoval Y, et al. High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study. Lancet 2015;386:2481-8.
5. Mueller C, Giannitsis E, Christ M, et al. Multicenter Evaluation of a 0-Hour/1-Hour Algorithm in the Diagnosis of Myocardial Infarction With High-Sensitivity Cardiac Troponin T. Ann Emerg Med 2016 Jan 8 [Epub ahead of print].
6. Cullen L, Mueller C, Parsonage WA, et al. Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome. J Am Coll Cardiol 2013;62:1242-9.
7. Carlton EW, Cullen L, Than M, Gamble J, Khattab A, Greaves K. A novel diagnostic protocol to identify patients suitable for discharge after a single high-sensitivity troponin. Heart 2015;101:1041-6.
8. Meller B, Cullen L, Parsonage WA, et al. Accelerated diagnostic protocol using high-sensitivity cardiac troponin T in acute chest pain patients. Int J Cardiol 2015;184:208-15.
9. Sanchis J, Bardají A, Bosch X, et al. Usefulness of high-sensitivity troponin T for the evaluation of patients with acute chest pain and no or minimal myocardial damage. Am Heart J 2012;164:194-200.
10. Challen K, Goodacre, SW. Predictive scoring in non-trauma emergency patients: a scoping review. Emerg Med J 2011;28:827-37.
11. Dunham M, Challen K, Walter D. Risk stratification of patients with acute chest pain without a rise in troponin: current practice in England. Emerg Med J 2010;27:461-4.
12. Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267-315.
13. Carlton EW, Khattab A, Greaves K. Identifying Patients Suitable for Discharge After a Single-Presentation High-Sensitivity Troponin Result: A Comparison of Five Established Risk Scores and Two High-Sensitivity Assays. Ann Emerg Med 2015;66:635-45.
14. Backus BE, Six AJ, Kelder JC, et al. A prospective validation of the HEART score for chest pain patients at the emergency department. Int J Cardiol 2013;168:2153-8.
15. Six AJ, Cullen L, Backus BE, et al. The HEART score for the assessment of patients with chest pain in the emergency department: a multinational validation study. Crit Pathw Cardiol 2013;12:121-6.
16. Mahler SA, Riley RF, Hiestand BC, et al. The HEART Pathway randomized trial: identifying emergency department patients with acute chest pain for early discharge. Circ Cardiovasc Qual Outcomes 2015;8:195-203.
17. Visser A, Wolthuis A, Breedveld R, ter Avest E. HEART score and clinical gestalt have similar diagnostic accuracy for diagnosing ACS in an unselected population of patients with chest pain presenting in the ED. Emerg Med J 2015;32:595-600.

Keywords: Acute Coronary Syndrome, Biomarkers, Chest Pain, Cohort Studies, Cost-Benefit Analysis, Diagnostic Tests, Routine, Electrocardiography, Follow-Up Studies, Myocardial Infarction, Outpatients, Prevalence, Prospective Studies, Randomized Controlled Trials as Topic, Registries, Risk Factors, Troponin I, Troponin T

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