A comprehensive review of upper reference limits reported for (high-)sensitivity cardiac troponin assays: the challenges that lie ahead

Cardiac troponins (cTn) are the preferred markers for the diagnosis of acute myocardial infarction (AMI). The guidelines recommend the use of the 99th percentile upper reference concentration of a healthy population as the diagnostic cut-off for AMI. However, a broad range of upper reference limits is still employed, complicating the diagnosis of AMI. This overview is meant to assist laboratory specialists to define an appropriate cut-off value for the diagnosis of AMI. Therefore, we provide an overview of the analytical performance and upper reference limits of seven (high-) sensitivity cTn assays: Roche high-sensitivity cTnT and ADVIA Centaur, Stratus CS, Dimension Vista, Vitros ECi, Access and Architect cTnI assays. It is shown that none of the reference populations completely met the guidelines, including those in package inserts. Forty percent of the studies collected less than the advised minimum of 300 subjects. Many studies (50%) did not report their inclusion criteria, while lower 99th percentile limits were observed when more stringent selection criteria were applied. Higher troponin cut-offs were found in men and elderly subjects, suggesting sex-and age-specific cut-offs would be considered. Therefore, there is still need for a large, rigorously screened reference population to more accurately establish cTn upper reference limits.