LAUSR

Circulation. 2019;139:562–563. DOI: 10.1161/CIRCULATIONAHA.118.037452 562 Yader Sandoval, MD Allan S. Jaffe, MD Fred S. Apple, PhD To the Editor: Several issues from the recent article1 concerning the Food and Drug Administration (FDA) meeting on cardiac troponin (cTn) assays from November 28, 2017, require clarification. The cTnT assay cleared by the FDA was approved as the “Troponin T Gen 5 STAT.” Recent approvals for the Beckman and Siemens cTnI assays were designed with high sensitivity. Although the FDA did not indicate criteria, they have embraced the recommendations of the Academy of the American Association for Clinical Chemistry and the Task Force on Clinical Application of Cardiac Bio-Markers of the International Federation of Clinical Chemistry, that high sensitivity refers to assays that measure cTn in ≥50% of healthy men and women and have a total imprecision (coefficient of variation, %) of ≤10% at the 99th percentile.2 The authors also suggest that the 99th percentile seems arbitrary. The rationale for the use of the 99th percentile for the Universal Definition of Myocardial Infarction was clearly articulated.3 It was because of the lack of precision of earlygeneration cTn assays to avoid false-positive results.3 This decision has served us well, and we doubt that the recommendations will be reversed. However, with high-sensitivity assays, the need to reduce variability in normal reference cohort studies has emerged. Expert consensus guidelines have been published on the number of subjects, ethnic and racial diversity, age range and sex, along with the use of surrogate biomarkers and the appropriate statistical method to permit more consistent calculations.2 The authors imply a shift away from the 99th percentile. This is incorrect. All major guidelines, including the 2014 and the 2015 European and American practice guidelines, and the latest Fourth Universal Definition of Myocardial Infarction,4 as well, endorse the use of the 99th percentile as part of the essential criteria for the diagnosis of acute myocardial infarction. The triage algorithms that the authors mention rely on those criteria. The authors appear to have confused these triage protocols that enhance the detection of myocardial injury with diagnosis. That use is in counter distinction to the use of high-sensitivity cTn assays for risk stratification where using lower concentrations than the 99th percentile clearly aid the process. The authors suggest that the data from the Universal Sample Bank of the Academy of the American Association for Clinical Chemistry clusters around the 99th percentile. In fact, there is a near-Gaussian distribution using high-sensitivity cTnI assays that have the ability to measure large numbers of reference subjects. That is different for the Gen 5 cTnT assay, which lacks comparable sensitivity and does cluster. Last, analyses of high-sensitivity assays should enroll all-comers undergoing cTn testing and avoid the use of insensitive gold standards for adjudication that falsely © 2019 American Heart Association, Inc. LETTER TO THE EDITOR Letter by Sandoval et al Regarding Article, “Designing a Better Mousetrap: Reflections on the November 28, 2017, US Food and Drug Administration Meeting on Next-Generation “High-Sensitivity” Cardiac Troponin Assays to Diagnose Myocardial Infarction” Circulation