A randomized clinical trial of sex and population-specific troponin cutoffs for ruling out acute MI - the danish study of sex and population-specific cutoffs of troponin (DANSPOT)

Abstract Background Measurements of high-sensitivity cardiac troponin (cTn) T/I are used as the gold standard and are the preferred biomarkers to diagnose acute myocardial infarction (MI) in conjugation with symptoms and changes in the ECG. The URL is based on the 99th percentile of troponin concentrations in a healthy reference population. Currently, a sex-uniform manufacturer provided 99th percentile URL of troponin is utilized at Danish hospitals as a diagnostic cutoff for acute MI for both men and women. Reportedly, healthy men have twofold the troponin level compared to healthy women, suggesting that the use of a uniform URL for troponins may lead to the under-diagnostication of acute MI in women and potentially over-diagnostication in men. Purpose The purpose of the DANSPOT study is to evaluate the clinical effect on diagnosis, treatment and outcomes in men and women presenting with acute MI of implementing international guidelines recommended sex-specific 99th percentile URLs for troponin into clinical practice. Methods First, to determine the sex-specific 99th percentile URLs of troponins (table) based on a healthy Danish reference population, blood samples from Danish blood donors, were analyzed using five high-sensitivity (hs) cTn assays (Siemens Atellica and Vista hs-cTnI, Roche hs-cTnT, Abbott Alinity hs-cTnI and Orthos VITROS hs-cTnI). Second, the DANSPOT study is a nationwide cluster-randomized trial with "stepped-wedge" design (figure) with participation of 22 Danish hospital center. With one-month intervals, each of the 22 centers have been randomized to shift from the presently applied sex-uniform 99th percentile URL of troponin to the population and sex-specific 99th percentiles URLs. First center started implementing the new 99th percentiles URLs on April 1, 2022, and the last center is planned to enroll on January 1, 2024. Patients are followed up in Danish registries for 12 months after index admission. The primary endpoint is a composite of myocardial infarction, unplanned revascularization (after index admission) and all-cause mortality and is calculated for the cohort of women and men with ≥2 measurements of troponin within the first 24 hours of admission with maximal troponin level between the new sex-specific 99th percentile URLs and the old sex-uniform 99th percentile URL. Perspective The clinical significance of sex-specific 99th percentile URLs of troponin is poorly investigated and for the same reason not yet implemented in Denmark or many other countries. With the implementation of population and sex-specific 99th URLs of troponin, we expect to detect significantly more women with acute MI, theoretically resulting in a more accurate diagnosis and treatment of women and men with acute MI. This would be guideline-defining for implementing sex-specific cutoffs for troponin in Denmark as well as internationally as recommended in guidelines by professional cardiological societies.Schematic presentation of study designTable of the new 99th percentiles of cTn