Elsevier

Clinica Chimica Acta

Volume 412, Issues 9–10, 11 April 2011, Pages 748-754
Clinica Chimica Acta

Multicenter analytical evaluation of a high-sensitivity troponin T assay

https://doi.org/10.1016/j.cca.2010.12.034Get rights and content

Abstract

Background

High-sensitivity cardiac troponin assays are being introduced clinically for earlier diagnosis of acute myocardial infarction (AMI). We evaluated the analytical performance of a high-sensitivity cardiac troponin T assay (hscTnT, Roche Diagnostics) in a multicenter, international trial.

Methods

Three US and 5 European sites evaluated hscTnT on the Modular® Analytics E170, cobas® 6000, Elecsys 2010, and cobas® e 411. Precision, accuracy, reportable range, an inter-laboratory comparison trial, and the 99th percentile of a reference population were assessed.

Results

Total imprecision (CVs) were 4.6–36.8% between 3.4 and 10.3 ng/L hscTnT. Assay linearity was up to 10,000 ng/L and the limit of blank and detection were 3 and 5 ng/L, respectively. The 99th percentile reference limit was 14.2 ng/L (n = 533). No significant differences between specimen types, assay incubation time, or reagent lots existed. A substantial positive bias (76%) exists between the 4th generation and hscTnT assays at the low end of the measuring range (< 50 ng/L). hscTnT serum pool concentrations were within 2SD limits of the mean of means in the comparison trial, indicating comparable results across multiple platforms and laboratories.

Conclusion

The Roche hscTnT assay conforms to guideline precision requirements and will likely identify additional patients with myocardial injury suspicious for AMI.

Introduction

Guidelines for the definition of acute myocardial infarction (AMI) were updated in 2007 by both clinical (American College of Cardiology/European Society of Cardiology/American Heart Association) and biochemical (National Academy of Clinical Biochemistry) expert groups, and these groups continue to recommend use of cardiac troponin (cTn; T or I) for diagnosis of AMI [1], [2]. cTn was chosen as the biochemical marker of choice due to its high myocardial specificity and sensitivity. Diagnostically, an increase or decrease in serial cTn concentrations is necessary to diagnose AMI, with at least one cTn concentration above the 99th percentile limit of the reference value distribution. This limit is usually derived by testing an apparently healthy population coupled with non-parametric statistical analysis. Analytical guidelines also continue to recommend an optimal coefficient of variation (CV) for troponin of ≤ 10% at the 99th percentile decision limit [1], [3]. For these reasons, newer generations of cTn assays now manifest not only improved analytical sensitivity but improved precision as well. Clinical studies have shown that interpretive decisions and initiation of treatment can be expedited as the cTn analytical sensitivity improves and if evaluation of changes in cTn concentrations is exploited [4], [5], [6]. As the next generation of high-sensitivity cTn assays comes to fruition, similar studies are needed to provide insight and allow for relevant information to be relayed clinically.

The logic driving the demand for high-sensitivity cTn assays stems from data which clearly demonstrates that the diagnosis of AMI can be made at an earlier time point if a highly sensitive cTn assay is utilized [7], [8], [9], [10]. In addition, more patients with co-morbid conditions who are at risk of adverse cardiovascular events are likely to be identified with highly sensitive assays [7], [11], similar to observations previously documented when earlier generations of assays improved analytical performance. Furthermore, with more sensitive assays a slightly increased cTn concentration above the 99th percentile, but which may lack a serial rise or fall, could be predictive for future adverse cardiovascular events and therefore has great potential to be used to identify and target patients at risk with primary prevention initiatives [12], [13].

In agreement with these premises, the newly developed Roche high-sensitivity troponin T (hscTnT) assay was designed to meet the analytical specifications necessary to enhance the current use of cTn in clinical practice. As rigorous analytical validation is essential for the newly proposed high-sensitivity cTn assays, due to the likelihood that modest analytic issues can have major adverse clinical effects [14], the purpose of this study was to comprehensively validate the analytical characteristics of the hscTnT assay in a multicenter international evaluation. This approach has advantages over a single center trial [15] as it interrogates the assay performance over a heterogenous array of laboratories and patient populations.

Section snippets

Study design

The multicenter evaluation of the Elecsys® hscTnT immunoassay was performed at 3 clinical sites in the United States and 5 clinical sites in Europe on fully automated Modular® Analytics E170 (3 sites), Elecsys® 2010 (5 sites), cobas® e 601 (1 site) and cobas® e 411 (2 sites) platforms according to a standardized protocol. Institutional Review Board approval was obtained at all participating sites. A familiarization trial, which evaluated inter-laboratory imprecision of control materials,

Assay imprecision

Results of the imprecision study are summarized in Table 1. Mean CVs of the Roche control materials ranged from 2.5 to 14.9% for the low control and 1.1–5.5% for the high control (total imprecision), respectively. The greatest intra- and total CVs were observed with the lowest concentration serum pools (hscTnT concentrations ranging from 3.4 ng/L to 10.3 ng/L) with a total imprecision CV range of 4.6–36.8%. The larger platforms (e 601 and E170, 18 min version of the assay) demonstrated superior

Discussion

Cardiac troponin has gained unquestionable acceptance as the gold standard biochemical marker for diagnosis of AMI. However, over the last decade cTn assays have been plagued with analytical imprecision issues that, together with the lack of standardization, have likely contributed to widespread variability of reported cutoff concentrations [20]. In response to the clinical emphasis placed on low cTn concentrations and the need for optimal analytical performance, manufacturers are increasingly

Acknowledgements

The authors acknowledge Brad Karon, Terry Gornet, Jerry Layton, and Sabine Radiske for their contributions and assistance with the study.

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