How to use high-sensitivity cardiac troponins in acute cardiac care

Recommendations for the use of cardiac troponin (cTn) measurement in acute cardiac care have recently been published.1 Subsequently, a high-sensitivity (hs) cTn T assay was introduced into routine clinical practice.2 This assay, as others, called highly sensitive, permits measurement of cTn concentrations in significant numbers of apparently illness-free individuals. These assays can measure cTn in the single digit range of nanograms per litre (=picograms per millilitre) and some research assays even allow detection of concentrations 10% at the 99th percentile URL limiting that ability.5–7 However, the less precise cTn assays do not cause clinically relevant false-positive diagnosis of acute myocardial infarction (AMI) and a CV 99th percentile URL is found in 37% of those with coronary plaques that are thought to be more labile or vulnerable.32,34 Up to 2% of the general population have been shown to have elevations of hs-cTnT above the 99th percentile URL in population studies.28,35,36 These individuals usually have either stable CAD, heart failure, renal failure, left ventricular hypertrophy, or these comorbidities in combination, reflecting other mechanisms including ischaemia causing cTn release.37 Therefore, hs-cTn elevations, indicating myocardial injury with necrosis must be interpreted in relation to the clinical presentation. However, regardless of the cause, elevations of hs-cTn values are associated with an adverse clinical outcome in most clinical conditions as in patients with AMI, stable CAD,32,34 chronic heart failure,29,33 acute pulmonary embolism, or chronic pulmonary arterial hypertension.38,39 Various considerations related to the criteria used have confounded the interpretation of the literature in this area. One problem relates to the fact that in many studies the diagnosis of AMI has been based on assays less sensitive than the hs-cTn assay being evaluated and at times, the cut-off values used have been higher than those recommended by guidelines (see above).27,40 This leads to apparent higher specificity with non-hs-cTn assays and lesser sensitivity and magnifies the differences in early sensitivities observed with the hs-cTn assays. Some patients may not have AMI diagnosed because their cTn values do not increase above the cut-off value of the less sensitive assay but do so with the hs-cTn assay. If so, a substantial number of patients with unstable angina may migrate from that designation to the AMI category. In addition, patients with CAD and an elevated hs-cTn are likely to be diagnosed as having AMI even if the values are not significantly changing. Such a group may comprise up to 14% of the patients diagnosed with AMI.41 As it is known that patients with stable angina may have elevations in hs-cTn,32 we may, by using an elevated hs-cTn value in isolation, include patients who have stable disease in the AMI category. All of these situations need to be considered in defining the minimum time course necessary to rule in AMI. Studies of the diagnostic performance of hs-cTn in a more heterogeneous populations are needed because most present studies have been done in pre-selected emergency department populations presenting with cardiac symptoms. Thus, the study design influences the sensitivity or the specificity of cTn, the optimal blood sampling regimens and optimal decision limits for absolute or relative changes in serial testing. The statistical analyses are also heterogeneous. Most studies determine optimal decision limits according to receiver operating characteristic analysis which weighs sensitivity and specificity equally; others have optimized cut-off values for specificity. The selection of criteria for change limits for AMI diagnosis will differ depending on whether there is a need for high specificity at the cost of lower sensitivity or increased sensitivity at the cost of lower specificity. Clinicians must be aware of this trade-off in evaluating individual patients. For these reasons, the pooling of study data from the literature is problematic. Key to the use of hs assays is the need to evaluate hs-cTn kinetics with serial testing in the clinical evaluation of chest pain patients.42,43 It should be recognized, however, that the application of any change criteria so far has been associated with an increase in specificity for AMI but at the price of a decrease in sensitivity.27,44 It should be clear that dynamic changes are not specific for AMI but are rather indicative of active myocardial injury with necrosis. Both the Joint ESC/ACCF/AHA/WHF task force for the universal definition of myocardial infarction and the National Academy of Clinical Biochemistry recommend a 20% change from an elevated cTn value as indicative of additional myocardial necrosis.9,43 This 20% change represents a significant (>3 standard deviations of the variation associated with an elevated baseline concentration) change in cTn on the basis of a 5–7% analytical total CV.43 This is the only metric that can be developed with conventional cTn assays. Assumptions of low imprecision are not valid when applied to cTn concentrations in the reference interval or around the 99th percentile URL with conventional cTn assays. Depending on the assay's CV at the baseline and follow-up sample concentration, changes may need to be much higher (up to 100–200%) to be outside of analytical variation, if baseline values are in the normal range or only slightly increased, i.e. above the 99th percentile URL but below the 10% CV value of the cTn assay. Changes of hs-cTn measurements near the 99th percentile URL also must exceed conjoint analytical and biological variation to be of clinical significance. With hs-cTn assays, one can now measure combined biological and analytical variation. This allows the calculation of the so-called reference change values (RCV) based on biological short-term (hourly) and intermediate-term (weekly) variation. Such values can be calculated only for reference individuals, but the theory of biological variation postulates the same process in patients with disease. These calculated RCV values are assay- and analyte-specific and must be obtained separately for each commercially available cTnT or cTnI assay. For many assays, short-term RCVs are in the 40–60% range45–47 although one report has values as high as 86%.48 Data on short- and long-term variation of hs-cTn concentrations in clinically stable patients with chronic cardiac diseases are very limited,49 but the reported variation is in the range of healthy individuals. Whether this RCV should be applied in patients with acute disease is a matter of debate. However, it should be appreciated that using change criteria below the reported RCV is likely to include some patients whose change could be explained by biological and analytical variation alone. This is of particular concern at concentration ranges around the URL, because, in general, most patients with definite acute cardiac events have substantial and obvious changes in hs-cTn values which are often considerably greater than the RCV.27,50,51 In contrast, it appears that changes in other diseases causing acute myocardial necrosis overlap substantially with those associated with AMI.41 It is very likely that with minimal changes (e.g. only 20% or less from a value in the normal range) an acute event can be ruled out. But if the clinical situation is ambiguous and the pre-test likelihood of disease is high, additional subsequent sampling is necessary (see Figure 1). Template for rapid early rule-in of acute myocardial infarction with high-sensitivity cardiac troponin displaying an algorithm for clinical use of high-sensitivity cardiac troponin testing based on current knowledge. It should be noted that the stated algorithm may vary according to the troponin assay evaluated. This approach optimizes sensitivity for acute myocardial infarction diagnosis, but clinicians may also wish to choose more stringent metrics to improve specificity (see text). AMI, acute myocardial infarction; hs-cTn, high-sensitivity cardiac troponin; URL, 99th percentile upper reference limit. *Evidence of ischaemia by symptoms and/or new electrocardiogram changes and/or new imaging corroboration. Whether the diagnostic performances of percentage change differ from an absolute change of cTn concentrations, has been tested with the hs-cTnT assay in recent clinical studies.44,51 They suggest that an absolute increase of hs-cTnT values (e.g. >7 ng/L over 2 h) is superior to a relative percentage changes from the baseline.44,51 It appears that most of this difference is due to patients who present late after the onset of symptoms and have higher values at baseline.51 Figure 1 provides a template for the use of hs-cTn in the early diagnosis of AMI. It is based on a consensus derived from the literature,52 which mainly has investigated hs-cTnT. The provided approach at least guarantees that the changes will be above the analytic variation. It is important to note that hs-cTn changes over a 3–6h period in patients presenting with subacute AMI may be 50% or absolute increases for hs-cTnT of >7 ng/L within 2 h suggest a rising pattern and optimize the overall accuracy of AMI diagnosis.44,51 For hs-cTnI, a recently published study evaluating serial changes using the Abbott® research hs-cTnI assay in pre-selected chest pain unit patients, suggested that increases above the 99th percentile URL with relative increases of >250% over a 3 h period optimize specificity for the diagnosis of AMI.40 However, the diagnosis in that study was based on clinical criteria and an increase in a standard cTn assay >99th percentile URL with a >20% change over a 6 h period. Higher sensitivities were found at lower percentage changes. Other hs-cTnI assays may require different metrics. On the basis of the available data on short-term biological variation,10 these changes likely will need to be at least >50% to exceed the RCV. The 99th percentile hs-cTn URL value should be used as the decision limit for the diagnosis of AMI in an appropriate clinical context. Documentation of a significant rise with serial testing is required. There is a need to use different cut-points for men and women in the future depending on the assay used.2,22–24 With higher-sensitivity assays, some groups, such as elderly individuals and diabetic patients, may have increased baseline cTn concentrations,35,36,53 because structural heart disease is so common in these patient groups. A recent publication suggested that it may be advisable to use a higher cut-point (about three-fold the 99th percentile URL) as a decision limit for AMI in >70-year-old patients.51 However, regardless of the cut-off value used, the critical distinction that must be made is to determine whether there is a significant rising and/or falling pattern of hs-cTn values as an indicator of acute myocardial necrosis. Use the 99th percentile concentration of the reference population as the cTn URL. The diagnosis of acute myocardial necrosis requires a significant change with serial testing. At low cTn baseline concentrations (around the 99th percentile), the change in serial testing in order to be clinically significant requires to be marked, in case of markedly elevated baseline, a minimum change of >20% in follow-up testing is required (see Figure 1). Additional testing of other early markers of acute myocardial necrosis, such as myoglobin or creatine kinase MB is no longer needed. Blood sampling in patients with suspicion of AMI should be performed on admission and 3 h of hs-cTn should be 6 h after admission in patients of the 3 h values are but in the clinical suspicion of AMI is still Cardiac troponin is a of myocardial necrosis and not a specific of AMI. The may be only diagnosed with a rise and/or of cTn with characteristic and/or electrocardiogram changes indicative of ischaemia and/or imaging evidence of acute myocardial also other of myocardial necrosis (e.g. acute heart failure or when an elevated hs-cTn test is or cTn values without significant dynamic changes are likely markers of chronic structural heart disease. 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