To put the matter in a nutshell: You can use both relative and absolute changes bearing in mind the level of baseline cardiac troponin (cTn) value and pre-test probability for acute myocardial infarction (AMI).

Table 1: Elevation of Cardiac cTn Values Other Than AMI Injury related to supply/demand imbalance of myocardial ischemia Stable CAD Tachy-/brady-arrhythmias Aortic dissection or severe aortic valve disease Cardiogenic, hypovolemic or septic shock Hypertrophic cardiomyopathy Severe anemia Severe respiratory failure Hypertension Coronary embolism or vasculitis Coronary spasm Coronary endothelial dysfunction without significant CAD Injury not related to myocardial ischemia Cardiac contusion, surgery, ablation, pacing, defibrillator shocks Rhabdomyolysis with cardiac involvement Myocarditis Cardiotoxic agents, e.g. anthracyclines, herceptin Multifactorial or indeterminate myocardial injury Heart failure Stress cardiomyopathy, e.g. Takotsubo Severe pulmonary embolism or pulmonary hypertension Critically ill patients Diabetic patients Elderly patients Renal failure Severe acute neurological diseases, e.g. stroke, trauma Infiltrative diseases, e.g. amyloidosis, sarcoidosis Extreme exertion Modified from Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012;60:1581-98.

According to current guidelines,1,2 AMI can be diagnosed when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Necrosis is defined as a significant rise and/or fall of cardiac cTn in addition to least one value above the 99th percentile. There is no statement in the universal definition of AMI about the change criteria: should clinicians use absolute or relative changes for diagnosis of AMI? What time interval is required for the cTn change to be diagnostic?

The introduction of hs-cTn assays has improved accuracy in the early diagnosis of AMI.3,4,5 These improvements in assay sensitivity have increased the number of positive hs-cTn results (cTn values >99th percentile) in conditions other than AMI, particularly those with structural heart disease who likely have chronic myocardial damage (e.g., chronic heart failure, stable coronary artery disease [CAD], left ventricular hypertrophy) [Table 1 and Figure 1].6,7 These conditions are sometimes difficult to distinguish from AMI. The use of serial measurements to determine changing cTn over time (delta cTn) is, therefore, recommended to differentiate between acute and chronic cTn elevations8 since in the majority of cases, chronic myocardial damages display no significant dynamic changes. In this context, it is important to remember that elevation of cardiac cTn is an indicator of myocardial cell damage (necrosis) but not necessarily caused by an (acute) MI.

Characteristics and Definition of New High-Sensitivity cTn Assays

The key differentiating feature of hs-cTn assays when compared with the conventional cTn assays is increased sensitivity, which is only apparent at values near the 99th percentile upper reference limit [URL]:9 hs-cTn assays provide a more precise calculation of the 99th percentile (upper reference limit [URL]) of cTn concentrations with a coefficient of variation (CV) <10%.10 hs-cTn assays are able to measure cTn concentrations 10- to 100-fold lower than conventional assays and are able to quantify cTn in ≥95% of normal individuals.11

Absolute or Relative Changes?

It is still unclear whether absolute or relative changes of cTn should be used for diagnosing AMI. It is a key requirement for both approaches that the respective change is above the analytic variation of the respective assay.

Two different approaches are currently used. The first is based on theoretical considerations regarding analytical and biological variability obtained from serial sampling in healthy volunteers12,13,14 as recommended in the 2007 NACB (National Academy of Clinical Biochemistry) practice guidelines.15 The second approach is data-driven based on large prospective cohorts of patients with acute chest pain.7,16,17,18

The NACB guidelines recommend a relative change of >20% (>3 SD of the coefficient of variation)15; however, they did not consider biological variation. Assuming that the difference in cTn values at two time points is determined through the underlying acute cardiac event as well as analytical and biological variability, the change in hs-cTn has to exceed the possible variability to be considered significant. Some groups12,13,14,19,20 measured biological short- and long-term variation of cTn to determine the reference change values (RCV) for intra-individual and inter-assay variability. Short-term biological variability was 14-58% at low ranges of hs-cTn as assessed in a healthy population, resulted in an RCV of 38-86%. Extrapolating these results to a cohort with suspected AMI is difficult because these comorbid patients are expected to have higher baseline hs-cTn values.

In the data-driven approach, absolute versus relative changes provided the highest accuracy to separate AMI from other causes of acute chest pain.13,14,15,17 The diagnostic superiority of absolute changes seems to be at least partly explained by the following: First, with the new hs-cTn assays even a small absolute increase or decrease in cTn in the normal range can lead to a large relative change, including patients without AMI. Second, the recommended relatively high relative changes (113 to 266%) 21, 22 often are not be reached by patients with AMI who present several hours after AMI onset as their cTn levels may already be close to the plateau.23

There were some differences in the results of two important studies mentioned above: whereas Reichlin et al.17 showed superiority of absolute changes independently of baseline hs-cTn values, Mueller et al.16 found absolute changes were superior only in patients with low and high baseline hs-cTn values (<14 and ≥100 ng/L). It seems that relative changes tend to over- (low baseline values) or underestimate (high baseline values) kinetic changes.

There are several limitations of the approach of absolute changes. Each individual hs-cTn assay will require a determination of absolute and relative change values because these can be influenced by the analytical and biological variability. The amount of the change criteria also depends on the population sample studied (e.g., cohort size, number of AMI, cardiovascular risk factors).

How to Use hs-cTn in Clinical Practice?

The introduction of hs-cTn assays has facilitated an earlier diagnosis and treatment of AMI at the cost of specificity. According to current guidelines for the use of hs-cTn in acute cardiac care,9 the application of any change criteria has been associated with an increase in specificity for AMI at the price of decreased sensitivity.17,22

Rule-In of AMI

Figure 2 shows an adapted and simplified approach for the rapid early rule-in of AMI using hs-cTn with cutoff criteria for changes based on baseline hs-cTn values24: Clinicians should use an absolute change of ≥50% and the 99th percentile at 3h in patients who have a baseline hs-cTn value ≤99th percentile, and a relative change of ≥20% at 3h in patients who have a baseline hs-cTn >99th percentile (Figure 2). The higher the baseline hs-cTn value, the higher the positive predictive value for an AMI. In cases with high baseline hs-cTn values, the delta value seems to be of less importance (Figure 1). A change is particularly relevant for diagnosing AMI if the baseline hs-cTn value is near the 99th percentile.

Rule-Out of AMI

Figure 1: The Differential Diagnosis of hs-cTnT Levels is Highly Dependent on the Absolute Level at Baseline Reproduced with permission from Twerenbold R et al. High-sensitive cardiac cTn: friend or foe? Swiss Med Wkly 2011;141:w13202.

A clear advantage of hs-cTn baseline and absolute delta values is the ability to rapidly exclude AMI. With recently published algorithms for hs-cTnT (Roche), hs-cTnI (Siemens and Beckman&Coulter) and cTnI ultra (Siemens)7,25 the rule-out of AMI seems to be possible in the majority of patients within one hour.

Despite the excellent performance of hs-cTn assays in the early diagnosis of AMI, the assays should be used only in conjunction with a detailed clinical assessment, i.e. their pre-test probability. The differential diagnosis of AMI versus myocarditis, Takotsubo cardiomyopathy or (malignant) arrhythmia might not be feasible with hs-cTn and necessitates further evaluation. In addition, despite its overall low sensitivity, the ECG remains an indispensable tool for immediately identifying patients who have an STEMI.26

Conclusions

Novel hs-cTn assays have led to an improvement in sensitivity for the early diagnosis of AMI. In order to maintain a high specificity early changes of cTn have shown to contribute substantially in the differential diagnosis of AMI – in particular with low baseline hs-cTn values.

Guidelines on precise application of delta values remain poorly defined. We believe it will be necessary to determine the delta change (absolute or relative) for every assay separately and to validate the clinical safety of the respective algorithms derived. For ruling-out AMI, absolute changes seem to be preferable, accurate and safe, especially in combination with baseline hs-cTn values. Algorithms for ruling-in AMI should always be used in clinical context with assessing the pre-test probability of AMI.

References

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Keywords: Troponin, Myocardial Infarction

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