See also pp. 490–501
In this issue of Emergency Medicine Australasia Jairam et al. report their findings on the clinical impact of using a new high-sensitivity troponin assay in a tertiary teaching hospital in New Zealand.1 Troponin testing was duplicated in patients in whom troponin (Tn) was ordered as part of their clinical management, using two assays: a 4th generation troponin T (cTnT) and the high-sensitivity TnT (hsTnT) assays. The authors aimed to identify changes in the positivity rate by using the high-sensitivity assay, and to characterize those patients in whom the hsTnT was positive, but the contemporary TnT was negative (the ‘new positive’ group). They described a significant increase in the numbers of patients with elevated troponin levels using the hsTnT assay (the ‘new positive’ group), but found that the diagnoses were often not AMI.
Few biomarkers in clinical use are as important as troponin, and yet so complex. Troponin levels continue to define patient populations, and determine the management of those patients presenting with a possible acute coronary syndrome.2,3 Recommended management guidelines for admission and monitoring practices, and the use of an invasive strategy exist for those found to be troponin positive; i.e. those with a non-ST-elevation acute myocardial infarction (NSTEMI). Improvements in the sensitivity and precision of troponin assays have occurred since the assay was first developed. This evolution has confused and challenged clinicians, and there has been limited consideration of the broad implications of this change to individual patients, the clinician and health services in general.
An elevated troponin has been defined as a value greater than the 99th percentile of a normal population.4 This value was rarely exceeded when using the early troponin assays, except in the setting of AMI. Historically, it was at this stage that troponin was therefore embraced as a ‘diagnostic’ test. Older biomarkers of AMI such as CK, CK-MB, aspartate amino transferase and lactate dehydrogenase became of limited importance. The conundrum of identifying a patient with AMI from the vast majority of ED patients with possible AMI symptoms appeared solved!
With each new generation of troponin assays, clinicians have been forced to relearn the utility of this biomarker in clinical practice. The list of causes for an abnormally elevated troponin has increased, mirroring the improvements in the assays and the lowering of detection limits. Elevations are seen in pathological conditions, including structural heart disease, renal impairment and pulmonary embolism, but might also be seen in extreme exertion, such as marathon runners.5,6 It is now clear that when using a highly sensitive assay, circulating levels of troponin will be detected in many normal people.7
Despite the definitions of AMI always including clinical features of ischaemia,3,8 once troponin measurements became available, this biomarker was often used by clinicians as the defining marker for AMI. This can no longer be so when using hs-troponin assays. The key for the diagnosis of AMI again lies in finding the correct clinical context of ischaemia. As clinicians, this leaves us with an inexact assessment science, as it is known that atypical presentations occur in up to 50% of all patients with AMI.9
The finding of biomarker evidence of acute myocardial necrosis is important. The increased positivity rate with newer troponin assays and the need to distinguish an acute elevation from a chronic one emphasizes the importance in identifying a change in troponin levels, i.e. a delta troponin. A ‘delta’, which represents the difference in troponin concentration over a fixed time period, can be characterized as a percentage increase, a change in absolute value, or as a rate of change.10,11 Specific recommendations for delta troponin values in clinical care have not yet been defined. Although the use of delta troponin will improve the specificity of the diagnosis of AMI, the finding of a delta in itself will not define a population with AMI. It will be essential to interpret any delta troponin result in the clinical context of that individual patient's presentation.
Thus, although the use of delta troponin sounds reasonable, it is much more complex than simply finding a change, as many parameters around delta values remain undefined (see Table 1). A newly proposed alternative method to clarify the cause of an increased troponin is to determine the half-life of its elevation. Ischaemia might cause blebbing of the myocyte cell membrane with release of small amounts of troponin that exist free within the cytoplasm (and not bound to myofibrils). This ‘ischaemic elevation’ of troponin has been shown to fall rapidly, in contrast to the persistent elevation seen with myocardial necrosis.12 Although it is proposed that the determination of troponin half-life will then assist in the identification of those with AMI, this will require lengthy serial testing, with the potential for a significant impact (increase) in the number of patients requiring medical admission as they await a second result.
The identification of those with a stable, chronic troponin elevation, in whom inpatient management might not be required, is also relevant. It might be that only patients with a changing elevation in troponin require admission, although again the clinical risk in this cohort is currently not defined.
Overall, our practice for ordering troponin will need to be urgently reviewed. Single troponin values will continue to be of little to no use in defining disease states in the ED. Identifying a chronic versus an acute elevation will only be revealed by serial troponin testing. The time interval between testing is currently contentious. Previous recommendations, including those by the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand and the American Heart Association, suggested that this interval should be at least 6–8 h after symptom onset.13,14 More recently, studies by Reichlin and Keller indicate that this time interval could safely be made significantly shorter when to as little as 2–3 h, using hs and some contemporary troponin assays.15,16 Some of these findings have been incorporated into the recent 2011 Addendum to the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand Guidelines for the Management of Acute Coronary Syndromes (ACS) 2006.17 These guidelines state that when using an hs-assay, repeat troponin testing might occur at a minimum of 3 h after presentation and at least 6 h after the onset of pain.
Jairam et al.'s paper identified the importance of the ordering practices for troponin. Where there is ‘no apparent reason’ for the test to be done, ordering must cease. There is a real risk of misdiagnosing conditions as a result of the distraction of finding an elevated troponin, or ‘troponitis’. This will become a much greater issue with the inevitable increased positivity rates expected using hs-assays.
So, how should clinicians best use the hs-troponin assay? As ED physicians, their use in the earlier ‘rule-in’ of AMI has been recognized,15,16 even though this early identification with aggressive management of those with a NSTEMI has not really been shown to dramatically improve clinical outcome (unlike those with a STEMI).18 Perhaps a greater interest lies in the ability of hs-Tn assay to allow the earlier ‘rule-out’ of AMI. Verification of this will allow accelerated assessment protocols to be developed, with patients rapidly progressing to provocative testing for inducible ischaemia at a much earlier time, even same day, following negative serial biomarkers and ECGs.
Although the finding by Jairam et al. that a larger proportion of patients are ‘troponin positive’ using the hs-assay is not surprising, it highlights in a real patient population the potential outcome of using this new generation Tn assay. The implications of doubling the positivity rate on individuals and the health system will need much careful investigation.
The large numbers of patients with a newly defined positive result will challenge us all, from the ED physician to the inpatient clinician; yet, there is undisputable evidence that this group is at higher risk of an adverse outcome. Evidence is also emerging that with aggressive management in this ‘new positive’ group there can be significant reductions in long-term morbidity and mortality.19 Thus, we cannot simply ignore this newly recognized group.
The advent of hs-assays in clinical practice is clearly a double-edged sword. As ED physicians we must seek to employ troponin testing only when an indication that improves patient care exists, including embracing their use to refine the ACS care process. However, a myriad of questions remain unanswered at this point in time. It is essential that ED physicians are involved in troponin research in patients with chest pain, and utilize standardized definitions to maximize the comparability of their data.20 There are fundamentally different objectives in the evaluation of these patients between ED physicians (who seek to ‘rule out’ and thus need a highly sensitive test to be negative), compared with cardiologists or internal medicine physicians (who seek to ‘rule in’ and thus need a more specific test to be positive).
Perhaps the key is to move away from defining AMI based on an absolute cut-off value for troponin, to seeing the troponin assay for what it really is – a risk-defining biomarker.