Early risk stratification in the emergency department (ED) for patients with potential acute myocardial infarction (AMI) is critical in patients presenting with chest pain.¹ Cardiac troponin (cTn), a biomarker of myocardial necrosis, used traditionally in conjunction with the ECG, forms the backbone for diagnosis of AMI.² Recently, high-sensitivity cardiac troponin (hs-cTn) assays are now available, can detect low levels of cTn previously undetectable by conventional assays, and have been shown in recent studies to lead to earlier detection of AMI.⁴

There is an ongoing debate regarding the role of hs-cTnT in diagnosis of AMI. Though the qualitative measurement of hs-cTn has been adopted by some centers across the world, 4th generation assay of cTn are currently in use in U.S.¹ A major criticism of the use of the hs-cTnT assay comes from its low specificity and positive predictive value (PPV), potentially leading to higher numbers of false positive diagnoses of AMI, resulting in a significant burden on hospitals.^5,6 Additionally, there have been concerns around the biological variability in the hs-cTnT assay levels across age and sex.⁷

The hs-cTn has been used both as a qualitative and a quantitative variable.⁴ Using hs-cTn, the proportion of patients who have AMI increases with increasing concentrations.² The traditional interpretation as a dichotomous variable (either a positive or a negative test based on a cut-off value used) leads to a low PPV for AMI diagnosis.⁵ Therefore, there has been an interest in using hs-cTn as a "quantitative" value to improve its diagnostic value.

To allay some of the concerns associated with use of hs-cTn for the purpose of AMI rule-in or rule-out in ED, Reichlin and colleagues performed a prospective study to validate a novel one-hour algorithm using hs-cTnT for the early rule-out or rule-in of AMI in patients presenting with chest pain in a large population.⁸ The algorithm combined a baseline level of hs-cTnT with an early absolute change in the concentration one hour later to provide incremental diagnostic value. A baseline hs-cTn level <12 ng/L and an absolute change within the first hour of <3 ng/L was defined as the level for "rule-out." To be ruled-in for AMI, the criterion was defined as either a baseline hs-cTn value of 52 ng/L or greater, or an absolute increase within the first hour of 5 ng/L or greater. Patients fulfilling neither of the above criteria for rule-in or rule-out were classified into an "observational" group.⁹ This hs-cTn one-hour algorithm, incorporating baseline values as well as absolute changes within the first hour, was validated against the final diagnosis which was adjudicated by two independent cardiologists using coronary angiography, echocardiography, follow-up data, and laboratory data, including subsequent hs-cTn levels.

This multicentre study was conducted across three countries (Switzerland, Spain, and Italy) in Europe.⁸ Among a total of 1,320 patients, 59.5% patients were classified as "rule-out," 16.4% as "rule-in" and 24.1% as an "observational group." AMI was the final diagnosis in 17.3% of patients. The sensitivity and negative predictive value (NPV) for A MI in the rule-out group were 99.6% and 99.9%, respectively. The specificity and the PPV for AMI in the rule-in group were 95.7% and 78.2%, respectively. Both the PPV and NPV of the one-hour algorithm were higher than the qualitative interpretation of hs-cTnT. As one would expect, with varying cut off values for baseline and one hour change in hs-cTnT levels, the specificity and PPV improved, but at the cost of sensitivity and NPV. The NPV and PPV were, however, both higher for the algorithm compared to a single baseline hs-cTn. The balance between the NPV and PPV achieved at one hour was comparable at two hours; however, approximately 24% of patients continued to remain in the observational zone at this time point. Lastly, the cumulative one month mortality rates in the rule out and observational zones were 0.0% and 1.6%.⁸ The authors concluded that the use of this algorithm could lead to safe and timely diagnosis of three out of four patients in the ED presenting with chest pain.⁸

Due to its higher sensitivity, hs-cTn can lead to an early diagnosis of AMI. In a recent study performed within the U.S. that compared hs-cTnT and 4th-generation cTn values (currently used in U.S.) in patients with a diagnosis of non-ST elevation AMI, use of the hs-cTnT assay improved risk stratification.¹⁰ This was, however, a retrospective study and only included patients with an AMI diagnosis.

There are several advantages of an early rule in of AMI with a high-sensitivity assay. In addition to the potential for reducing mortality and morbidity associated with delay in institution of definitive therapy or interventions in AMI, timely rule-out helps in reducing unnecessary burden on hospital resources, streamlines ED throughput, helps allay patient's anxiety and reduces unnecessary testing.

However, use of the hs-cTn for stratification of chest pain patients in ED is fraught with challenges. The low specificity of hs-cTn is a large limitation of this assay, especially in the elderly, as are the frequent elevations found in the presence of heart failure and renal disease. It is to be noted that one in four patients were still not correctly risk stratified by the algorithm used in the above analysis.⁸

Chronic elevation in hs-cTnT levels are not uncommonly seen in the general population¹³ and are possibly the largest challenge with its use. Herein lays the utility of a "δ" hs-cTnT value in making a diagnosis of AMI, rather than just relying on the baseline value. However, defining the optimal "δ" in itself may be challenging and will likely need to be individualized based on the underlying risk profile of the patient and the specific assay used. Currently multiple different assays currently exist for hs-cTn with different sensitivities and specificities for AMI diagnosis.¹¹ How this would affect the uniformity of algorithm used for diagnosis of AMI is unknown. Cost effectiveness of an hs-cTn algorithm for ED would be of critical. Importantly, a recent analysis found that hs-cTn appeared promising in terms of overall cost reduction.¹²

The algorithm described by Reichlin et al. is certainly one step closer to achieving a near perfect biomarker strategy for diagnosis AMI in patients presenting to ED with chest pain, but the complexity of the algorithm does raise questions on the ease of its adoption universally. One way would be to incorporate built-in algorithms in the electronic medical record with automatic calculation of "δ" between consecutive hs-cTn values and flagging abnormal values.

In conclusion, the future looks bright for the use of hs-cTn in triage of patients with chest pain in the ED; however, there is still a need for further fine tuning of these algorithms and their application in the real world. Finally, it needs to be reiterated that though such algorithms are extremely useful for triaging patients with chest pain in ED, they always need to be used in conjunction with the clinical presentation, including obtaining a good history as well as abstraction of available clinical data to come to a more accurate diagnosis.

References

1. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127:663-828.
2. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012;60:1581-98.
3. Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009;361:868-77.
4. Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 2009;361:858-67.
5. Reichlin T, Irfan A, Twerenbold R, et al. Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction. Circulation 2011;124:136-45.
6. Newby LK. Myocardial infarction rule-out in the emergency department: are high-sensitivity troponins the answer?: comment on "One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T". Arch Intern Med 2012;172:1218-9.
7. de Lemos JA, Drazner MH, Omland T, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA 2010;304:2503-12.
8. Reichlin T, Twerenbold R, Wildi K, et al. Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a high-sensitivity cardiac troponin T assay. CMAJ 2015;187:E243-52.
9. Reichlin T, Schindler C, Drexler B, et al. One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Arch Intern Med 2012;172:1211-8.
10. Grinstein J, Bonaca MP, Jarolim P, et al. Prognostic implications of low level cardiac troponin elevation using high-sensitivity cardiac troponin T. Clin Cardiol 2015;38:230-5.
11. Apple FS. A new season for cardiac troponin assays: it's time to keep a scorecard. Clin Chem 2009;55:1303-6 .
12. Westwood M, van Asselt T, Ramaekers B, et al. High-sensitivity troponin assays for the early rule-out or diagnosis of acute myocardial infarction in people with acute chest pain: a systematic review and cost-effectiveness analysis. Health Technol Assess 2015;19:1-234.
13. Omland T, de Lemos JA, Sabatine MS, et al. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med 2009;361:2538-47.

Keywords: Acute Coronary Syndrome, Aged, Algorithms, Anxiety, Biomarkers, Chest Pain, Coronary Angiography, Cost-Benefit Analysis, Early Diagnosis, Echocardiography, Electrocardiography, Electronic Health Records, Emergency Service, Hospital, Follow-Up Studies, Heart Failure, Myocardial Infarction, Prospective Studies, Retrospective Studies, Sensitivity and Specificity, Triage, Troponin

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