Troponins are a family of structural proteins found in muscle fibers that damaged muscle releases into the bloodstream. Troponin I and T are specific to heart muscle, and therefore, measurement of an elevated troponin I or T supports the diagnosis of cardiac muscle disease or injury.
Troponin I or T measurements for acute myocardial infarction (MI) diagnosis were introduced into practice in 1995 and became the preferred laboratory test (versus traditional cardiac enzymes) in 2000 (1,2). Troponin levels greater than the 99th percentile of the reference population (upper reference limit, or URL) indicate myocardial injury (3). In acute myocardial injury, troponin I or T levels show a rising and/or falling pattern; in chronic myocardial injury, troponin I or T levels remain elevated above the 99th percentile URL (3).
It is imperative to understand the performance characteristics of a specific assay being used for patient care (4). Current professional society recommendations have defined standards for allowable imprecision at the 99th percentile URL, measured by coefficient of variation, as <10% (5). However, initial troponin assays were limited by the ability to precisely measure concentrations at very low levels.
Technological advances in the development of troponin assays have allowed for increased precision at levels lower than the 99th percentile, in the area previously considered to be “normal range.” The assays have become so precise that they can achieve <10% coefficient of variation approaching their lowest concentration of detection. Hence, newer definitions of “high- sensitivity troponin” (hs-cTn) require <10% imprecision at or below the 99th percentile URL and the ability to detect troponin in 50% of healthy individuals (4).
Transitioning to A Continuous Variable
The dramatically improved precision creates an uncommon paradigm change in clinical medicine where an assay previously considered in a largely binary fashion is transitioning to one where the results must be interpreted with greater nuance. This is arguably a natural advancement in test use. Troponin is, after all, a continuous variable. The 99th percentile threshold used as a key determinant of myocardial infarction (MI) and injury is relatively arbitrary, varies between populations, and even changes according to the statistical technique used to account for outliers (6).
If implemented well, the improvements in precision offer an opportunity to reduce the number of missed MIs and perhaps also reduce the number of patients admitted to the hospital. If implemented poorly, the new assays could result in increased hospitalizations or increased demand on cardiovascular services, including consultations and diagnostic tests.
How To Plan Implementation of High- Sensitivity Troponin Assays
If a hospital decides to transition to a hs-cTn assay, what comes next? For some clinicians, this can provoke anxiety. However, if done well, it can change how you provide care within your health system.
There are six keys in preparing for hs-cTn assay implementation: 1) identify best practices of other institutions, 2) identify key stakeholders and meet regularly to plan the transition, 3) communicate the change to the all clinical staff who contribute to the management of patients with suspected chest pain (and also those who might deal with abnormal hs-cTn assays), 4) make the change, 5) expect uncertainty post-implementation and adjust accordingly, and finally, 6) assess your outcomes (8). Januzzi, et al., have provided a detailed framework and checklist of how to systematically approach the transition from the lab, emergency department (ED), or hospital perspective (9).
Proper preparation can take up to a year or more based on your lab’s validation, cut point determinants, and integration into the electronic health record (EHR) while the ED and hospital are working on consensus for the timing of serial testing and the utilization of an accelerated diagnostic protocol. Providers and staff need extensive education to understand the differences from their contemporary assay and the 4th universal definition of MI prior to implementation (10, 11).
Timing of Testing and the Accelerated Decision-making Pathway
It is worth noting that the threshold used to indicate a positive troponin test result was once approximately ten times higher than the 99th percentile thresholds used now. As a result, it was not unreasonably felt that it could take some time from symptom onset for measurable troponin concentrations to meet such a threshold. It was commonplace for tests to be repeated after 12 hours or the following morning after admission.
One of the key benefits of high-sensitivity troponin is the ability to measure both very low concentrations and changes to low concentrations with high precision and confidence. The timeframe between symptom onset and reliable detection of very low concentrations of troponin (or concentration changes) can now be much shorter. This has led to clinical pathways that incorporate troponin measurement at 0 and 6 hours then 0 and 3 hours, using the 99th percentile as a decision threshold. Subsequently, pathways have been written using 0- and 2-hour blood sampling, but more recently, pathways have incorporated other thresholds in addition to (and sometimes instead of) the 99th percentile for decision-making have also been developed.
The expression "accelerated decision-making or diagnostic pathway" (ADP) is often used to describe decisionmaking strategies that combine troponin with ECG findings and risk assessment (usually in a structured format). Examples of such ADPs incorporate risk assessment aids such as the HEART score, TIMI score, EDACS (Emergency Department Assessment of Chest Pain Score) and MACS (Manchester Acute Coronary Syndromes).
Newer strategies that are troponin-based, such as the European Society of Cardiology Guidelines and High-STEACS (High-Sensitive in the Evaluation of Patients with Acute Coronary Syndrome), demonstrate the use of single test and dynamic change (delta) decision-making without a focus on the use of a risk score.
For a high-sensitivity assay there will be a very low troponin concentration threshold (often near the level of detection or limit of quantification) that can be used for rule out of MI after a single troponin concentration measurement (provided the patient is not a very early presenter following symptom onset—a timeframe of 2 or 3 hours is often used). Suggested delta change thresholds for each troponin assay can be found in the latest iteration of the ESC Guidelines (6).
The overall impact of using single tests and early delta change for decision-making means that a marked proportion of patients (20−40%) can be discharged from the ED following a first test result. A further 30−50% can be discharged after the result from a second troponin drawn 1 or 2 hours after the first, meaning that it is possible to discharge approximately 60% of patients from the ED within a short timeframe.
This is a dramatic shortening from the historical timeframes required for safe rule out of MI from the past, and such pathways have an important impact on ED and hospital crowding.
Delta Analysis
Delta values represent the difference between two values. In this context, deltas represent the change over time, with large changes representing increased likelihood of acute myocardial damage. A patient with elevated troponins that do not change over time is likely to have chronic myocardial damage or decreased excretion of the protein through the kidney.
In a procedure that includes three troponin levels, a total of three deltas are possible: the first value versus the second, the second versus the third, and the first value versus the third. Institutions must decide if they will report all three or the “max delta,” which may change after the third troponin level is determined.
Additionally, institutions must decide if they will utilize and report the delta as a whole number difference (the absolute value of one value minus another value) or as a percentage difference between values. Generally, troponin deltas are viewed as whole positive numbers (absolute values) as either a rise or fall in troponin overtime is indicative of an acute event.
Finally, delta values should be verified as part of a reference range in an institution’s patient population. In our system, deltas were calculated by the electronic health record when a value obtained at any time point was greater than the limit of detection (LOD) of 6 pg/mL and less than 99 pg/mL. The delta was reported as a “max delta” so that whichever delta was highest between 0 and 1 hours, 0 and 3 hours, or 1 and 3 hours would be reported. Deltas were always reported as positive, whole numbers. In other words, if the troponin changed in a falling pattern, the delta was still reported as a positive number (12). Following our initial testing strategy, our system has moved to a 0- and 2-hour pathway with a single troponin option for those who have had symptoms for greater than 3 hours and the value is below the LOD.
Cardiology’s Perspective on Go-live and Assessments
As cardiac biomarkers like troponin have continued to improve in sensitivity clinicians, are less and less likely to miss a clinically important acute cardiac event. This improvement is undoubtedly beneficial for patients with acute coronary syndromes (ACS), especially for those who might benefit from an invasive management approach. On the other hand, when looking at the whole population of patients with abnormal levels of circulating troponin, it becomes more challenging to interpret results in order to determine which patients will benefit from additional cardiac testing and/or invasive procedures.
Multiple large-scale cohort studies have helped us understand the scope of this challenge. The CHARIOT study gathered samples from a consecutive cohort undergoing blood tests for any reason and found that 5.4% (n=1,080 of 20,000) had hs-cTn concentrations above the 99th percentile. Once elevated hs-cTn is detected, an in-patient team (often cardiology) is responsible for distinguishing Type 1 MI from from Type 2 MI. This task is not as straightforward as one might suspect: The proportion of patients with Type 2 MI varies wildly from <5% to >70%, owing to differences in population but also differences in how the Universal Definition of MI is applied. Among those with a suspected ACS, Type 1 and 2 MI may represent the minority of those with elevated hs-cTn, as little as one third in some cohorts. Despite relatively specific diagnostic criteria and recommendations on how to interpret patterns of rise/fall of hs-cTn, some clinicians find the definitions arbitrary, and the criteria depend highly on interpretation of historical symptom details provided by the patient.
With so many patients who have elevated hs-cTn, some clinicians are concerned about switching to the hs-cTn assay because of the potential for overwhelming demand on resources already stretched too thin. Projections from a variety of sources suggest the U.S. healthcare system will continue to suffer from a shortfall in cardiologists and adequately trained advanced practice providers. Thankfully, most available data seems to show that, for the inpatient setting, the demand for cardiac testing and consultations does not dramatically increase with transition to hs-cTn and may reduce admissions and length of stay (13, 14).
The other remaining question that looms over cardiologists about hs-cTn is ongoing management. Data are lacking on which patients may benefit from additional structural, perfusion, and coronary anatomic assessment. Although studies like the ISCHEMIA trial are reassuring that stable ischemia heart disease may be managed medically, no similarly impactful large-scale studies have evaluated hs-cTn elevations due to chronic or acute MI.
Patients with Type 2 MI who are referred to a cardiologist are more likely to have factors associated with mortality, and the patients are much more likely to undergo cardiac testing. But any improvement in outcomes is unclear at this point. Optimal management should be a high priority for the cardiology community, as multiple lines of evidence have demonstrated that outcomes are worse for Type-2 MI patients compared to Type-1 MI.
Conclusion
The evolution of the assessment of ACS has led to improved precision and management of these patients with hs-cTn as the primary biomarker. There are many topics and challenges to consider when your hospital or health system is transitioning to a high sensitivity troponin assay. Thankfully, a framework has been developed in the literature to support decisions leading to improved safety and efficacy while also enhancing the management of patients with defined acute myocardial injury or infarction.
References
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- Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000; doi: 10.1016/s0735-1097(00)00804-4.
- Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Eur Heart J 2019; doi: 10.1093/EURHEARTJ/EHY462
- Apple FS. A new season for cardiac troponin assays: It’s time to keep a scorecard. Clin Chem 2009; doi:10.1373/clinchem.2009.128363
- Thygesen K, Alpert JS, Jaffe AS, et al. ESC Committee for Practice Guidelines (CPG). Eur Heart J 2012; doi:10.1093/eurheartj/ehs184
- Collet J, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021; doi: 10.1093/eurheartj/ehaa575
- Mueller C, Boeddinghaus J, Nestelberger T. Downstream consequences of implementing high-sensitivity cardiac troponin: Why indication and education matter. J Am Coll Cardiol 2021; doi:10.1016/J.JACC.2021.04.063
- Hollander JE. High-sensitivity troponin: Time to implement. Ann Emerg Med 2018; doi:10.1016/J.ANNEMERGMED.2018.07.025
- Januzzi JL, Mahler SA, Christenson RH, et al. Recommendations for institutions transitioning to high-sensitivity troponin testing: JACC scientific expert panel. J Am Coll Cardiol 2019; doi:10.1016/J.JACC.2018.12.046
- Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Eur Heart J 2019; doi:10.15829/1560-4071-2019-3-107-138
- 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; doi:10.1016/j.ijcard.2015.02.006
- Beal SG, Winchester DE, Wilkerson G, et al. Comparison of patient results on a new high-sensitivity troponin I assay with a conventional assay, focusing on clinically relevant cutpoints. J Appl Lab Med 2020; doi:10.1093/JALM/JFAA014
- Winchester DE. Implementation of a High-Sensitivity Troponin-I Assay in an Academic Medical Center: A Qualitative and Quantitative Assessment. J Invasive Cardiol 2021 Jul;33(7):E549-E556.
- Winchester DE. Implementation of high sensitivity troponin in a veterans health system: lessons learned. Vessel Plus 2021; doi:10.20517/2574-1209.2020.53
Brandon R. Allen, MD, FACEP, is associate professor and vice chair of clinical operations; associate chief of emergency services; and medical director at the University of Florida Health Chest Pain Center in Gainesville, Florida. a href="mailto:[email protected]">+Email: [email protected]
Stacy G. Beal, MD, is an associate professor in the department of pathology, immunology, and laboratory medicine at the University of Florida in Gainesville, Florida. She is the associate medical director of the core laboratory and medical director of the microbiology laboratory. +Email: [email protected]
David E. Winchester, MD, FACC, FACP, FASNC, is professor of medicine at the University of Florida College of Medicine and staff cardiologist at the Malcom Randall Veterans Affairs Medical Center in Gainesville, Florida. +Email: [email protected]
Martin P. Than, MBBS, FACEM, is director of emergency medicine research at Christchurch Hospital, New Zealand. +Email: [email protected]