Troponins in Acute Coronary Syndromes: Title and subTitle BreakMore TACTICS for an Early Invasive Strategy

Cardiac isoforms of troponin I (cTnI) and T (cTnT) are highly sensitive and specific markers of myocardial injury. Elevations of either of these proteins in the setting of an acute coronary syndrome (ACS) identify patients with a several-fold increased risk of death in subsequent weeks.¹ The prognostic importance of these markers likely stems from their ability to detect microscopic amounts of myocardial necrosis that result from a severe epicardial stenosis or distal embolization of friable atherothrombotic debris overlying the unstable coronary plaque.² As such, troponin-positive patients often have complex coronary lesion morphology with intracoronary thrombus,³ and understandably derive particular benefit from platelet glycoprotein (Gp) IIb/IIIa inhibitors^{4 - 6} as well as low-molecular-weight heparins.⁷

In this issue of THE JOURNAL, Morrow and colleagues⁸ present the results of their prespecified subanalysis of cTnI or cTnT levels obtained at the time of randomization in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)–Thrombolysis in Myocardial Infarction (TIMI) 18 trial of different management strategies for patients with ACS. The authors observed a marked reduction (50%-53%) in ischemic events among troponin-positive patients randomized to an early (between 4 and 48 hours) invasive strategy added to a background of Gp IIb/IIIa inhibition and heparin therapy. Importantly, the capacity of troponins to predict a benefit from an invasive approach was superior to that of ST-segment deviation or creatine kinase (CK-MB) elevation.

These findings strongly support an early invasive strategy for troponin-positive patients with ACS and re-emphasize the relationship between elevated troponin levels and an increased risk of morbidity and mortality. Some caution is needed, however, before adopting this strategy. While Morrow et al used commercially available cTnI and cTnT assays, the testing was performed in a dedicated core laboratory. In current clinical practice, many cTnI and cTnT assays are available. These are based on the binding of specific monoclonal antibodies to the cardiac troponin isoforms and include quantitative laboratory-based assays and qualitative (positive or negative) or semiquantitative point-of-care assays, which provide rapid troponin estimations at the bedside. Prudence is needed in interpreting the results from point-of-care tests, as their correlation with central laboratory assays may be poor⁹ and most of the data regarding the prognostic importance of troponin elevations are based on central laboratory testing. Furthermore, at the low-level cTnT elevations (0.06-0.18 ng/mL) used by Morrow et al, there is considerable intraobserver and interobserver variation in the discrimination of a positive test result.¹⁰

Laboratory-based assays overcome these problems by using quantitative methods. However, standardization between individual cTnI assays is poor and measured levels may vary by a factor of 20 or more.¹¹ Much of this variation relates to differing affinities of the antitroponin antibodies used in these assays. To address these issues, the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) recommend that individual laboratories define their reference values and that an increased value for cTnI be defined as a measurement above the 99th percentile of a normal control group.¹² Thus, reference ranges may vary depending on the assay used and the population studied.

In addition to problems with standardization, the precision of some of these assays is poor. The precision of an assay refers to the degree of random error and the reproducibility of measurement. Precision is usually measured by repeated analysis of an individual sample. This produces a range around the true value, the extent of which is described as the coefficient of variation (CV). The CV is calculated by dividing the SD by the mean of the results obtained from multiple measurements. The precision of an assay typically diminishes and the CV usually increases as the assay approaches the limit of detection. The ESC/ACC Committee recommend that the CV, or acceptable imprecision, at the 99th percentile should be less than 10%. When Morrow et al used these recommendations to set their decision-limit for cTnI at a CV of 10% (0.4 ng/mL), 181 patients were inappropriately classified as troponin negative although they had a risk equivalent to that of the patients with cTnI levels of 1.5 ng/mL or higher. Thus, even with these precautions there is the potential for misclassification of a considerable number of high-risk patients.

It is important to be aware of these factors as every busy clinician has been frustrated by both occasional false-positive troponin results and other cases in which the troponin result is negative even though the CK-MB level is frankly elevated. The presence of jaundice¹³ or the concurrent use of heparin¹⁴ has been shown to result in underestimation of troponin in some cases, while false-positive results can occur in the presence of sepsis,¹⁵ fibrin clots, heterophile antibodies,¹⁶ and rhabdomyolysis.¹⁶ Furthermore, unexpected troponin elevations, involving both cTnT and cTnI, can occur in patients with severe renal disease.¹⁷ These elevations were initially thought to be nonspecific, due to cross-reactivity of the early troponin assays with the skeletal muscle isoforms; however, these elevations are also predictive of outcome and should not be considered nonspecific.¹⁸ Low-level elevations of troponin also have been documented in patients with pulmonary emboli, pericarditis, or cardiomyopathies,^{19 - 21} probably as a result of concomitant mild cardiac damage. Due to these interassay and laboratory shortcomings, the crux of appropriate interpretation of troponin testing is careful consideration of the corresponding clinical scenario. As pointed out by Morrow et al, their findings are relevant to patients with typical presentations of unstable angina and ACS and should not be generalized to patients with a low clinical suspicion of coronary artery disease.

Thus, the findings of Morrow et al represent an important advance. Even a minor elevation of troponin in the appropriate clinical setting of ACS identifies patients who will benefit from an early invasive approach. However, the imprecision and lack of standardization of currently available troponin assays merit caution with the application of their findings.