High-Sensitivity Cardiac Troponin Assays: What Analytical and Clinical Issues Need to Be Addressed before Introduction into Clinical Practice?

The guidelines of the Global Task Force for the Universal Definition of Myocardial Infarction (MI)1 and the complementary laboratory medicine practice guidelines of the National Academy of Clinical Biochemistry (NACB), both published in 2007, established cardiac troponin (cTn) as the standard biomarker for the diagnosis of MI. Ongoing improvements in technology over the past several years have advanced the analytical detection of low concentrations of cTn (I and T) in blood, serum, and plasma. “Contemporary” assays demonstrate excellent diagnostic accuracy for detection of MI by using the recommended 99th percentile concentration as the medical decision cutoff value in specimens obtained at presentation. Optimal accuracy is seen with these assays in samples obtained 6 or more hours after presentation. However, there are 2 important biomarker issues mentioned in these guidelines that will be critical in defining the next and possibly final generation of high-sensitivity (hs) cTn assays. (1) In both guidelines, total assay imprecision is recommended but not required to be ≤10% at the 99th percentile. As previously shown and discussed in the literature, cTn assay imprecision ≤20% CV at the 99th percentile value does not lead to substantial increases in false-positive or -negative misclassifications. (2) Whereas study of a normal reference population is advocated in both guidelines for calculation of the 99th percentile before assay implementation in clinical practice, the specifications of that population (age, sex, ethnicity, race) and the number of individuals that should be included in the “normal” group have not been clearly stipulated. An opinion paper recently published in this journal suggested that hs-cTn assays need to have a total imprecision ≤10% at the 99th percentile and that >95% of apparently healthy subjects need to have measurable concentrations for the assay to be “guideline acceptable.” An assay with an imprecision between >10% and ≤20% was deemed …