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

Abstract

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 <1 ng/L.2–4 Thus, they provide a more precise calculation of the 99th percentile of cTn concentration in reference subjects (the recommended upper reference limit [URL]). These assays measure the URL with a coefficient of variation (CV) <10%.2–4 The high precision of hs-cTn assays increases their ability to determine small differences in cTn over time. Many assays currently in use have a CV >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 <20% at the 99th percentile URL is still considered acceptable.8 We believe that hs-cTn assays, if used appropriately, will improve clinical care. We propose criteria for the clinical interpretation of test results based on the limited evidence available at this time. ‘Sensitive’ and ‘high-sensitive’ are terms often used by manufacturers to describe their assays for marketing purposes. In some cases, it reflects higher sensitivity than former assays developed by the same company, and in other situations it reflects a higher sensitivity than most assays on the market. Although there is still no consensus regarding when the terms ‘sensitive’ and ‘high-sensitive’ should be applied, we advocate that cTn assays should be labelled ‘high-sensitive’ only if they fulfil the analytical criteria suggested by guidelines1,9,10 not only in the research laboratories of the manufacturers but also in routine clinical laboratories.11–19 Often manufacturers' claims for assay precision cannot be achieved in clinical laboratories (see Table 1). It is also important to note that there may be substantial differences between ‘high-sensitivity’ assays. Most present cTn assays do not detect even in 50% of apparently disease-free individuals20 whereas high-sensitivity assays do and with some, detection may be as high as in 90%.4,20,21 In addition, reports for the hs-cTnI Singulex®, the hs-cTnT, and the Abbott® hs-cTnI assays suggest a need for different 99th percentile values in men and women, although that does not seem to be the case with the hs-cTnI Beckman® research assay.2,21–24 Peer-reviewed analytical evaluation data on cardiac troponin assays approved for routine diagnostics In addition, hs-cTnI assays fulfilling the analytical criteria of guidelines have been developed by Beckman®, Nanosphere®, Singulex®, and Siemens®, which are still in the pre-marketing phase but may also become available for routine use subsequently. None of the currently commercially available cTn assays except for the hs-cTnT and the yet to be approved hs-cTnI assay from Abbott Diagnostics meets the proposed criteria for a high-sensitivity assay in routine use. It is important to differentiate between the LoB and the LoD, because these terms are frequently not correctly used in the cTn literature. The LoB is the highest signal in a test which can be expected from a sample without the analyte, in contrast the LoD is the lowest concentration of an analyte in a sample which reliably can be differentiated from a sample without the analyte. The LoD is always higher than the LoB. NA, not available; LoB, lower limit of blank; LoD, lower limit of detection. aBench-top systems suitable for point-of-care (POC) analysis but no hand-held POC devices. bNot approved by the US Food and Drug Administration so far. cMay be approved for routine use in Europe in 2012. Peer-reviewed analytical evaluation data on cardiac troponin assays approved for routine diagnostics In addition, hs-cTnI assays fulfilling the analytical criteria of guidelines have been developed by Beckman®, Nanosphere®, Singulex®, and Siemens®, which are still in the pre-marketing phase but may also become available for routine use subsequently. None of the currently commercially available cTn assays except for the hs-cTnT and the yet to be approved hs-cTnI assay from Abbott Diagnostics meets the proposed criteria for a high-sensitivity assay in routine use. It is important to differentiate between the LoB and the LoD, because these terms are frequently not correctly used in the cTn literature. The LoB is the highest signal in a test which can be expected from a sample without the analyte, in contrast the LoD is the lowest concentration of an analyte in a sample which reliably can be differentiated from a sample without the analyte. The LoD is always higher than the LoB. NA, not available; LoB