Counterpoint: Potential Concerns Regarding the Use of Sex-Specific Cutpoints for High-Sensitivity Troponin Assays

Abstract

There are biological differences between males and females in cardiac structure and function that have been recently revealed using sensitive imaging techniques such as magnetic resonance tomography (1 ). With the availability of more sensitive assays capable of measuring extremely low concentrations of cardiac troponin, such biological differences may contribute to 99th percentile reference values for cardiac troponin that have been found to be lower in women than in men (2 ). Although it is still unclear whether clinical evidence is strong enough to support the use of sex-specific cutoffs in clinical practice, the Joint ESC/ACCF/AHA/WHF (European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Heart Federation) Task Force for the Universal Definition of Myocardial Infarction already recommends the use of sex-specific cutoffs (3 ). However, there are several reasons to question such a general recommendation including a lack of consistent clinical evidence, the need to validate such criteria for each high-sensitivity (hs) 2 cardiac troponin assay owing to potential analytical differences between assays, and the wide variation in 99th percentile values across commercially available cardiac troponin assays (4 ). These issues may confuse clinicians and translate into the incorrect incorporation of such limits into clinical routine as diagnostic algorithms become increasingly complicated.In particular, there are 5 relevant concerns that argue against such a recommendation and that require more elaboration.1. Clinical evidence supporting the use of sexspecific cutoffs is sparse and controversial. Application of sex-specific 99th percentile values (4 ) was reported to increase numbers of non-ST elevation myocardial infarctions (NSTEMIs) by 4.7%-11% in females depending on the hs-cardiac troponin assay used, but also to decrease numbers of NSTEMIs in males by 2%-3% (5-7 ). Whether diagnostic reclassification translates into improved prediction of outcomes is a matter of controversy with some studies reporting an unequivocal benefit (5 ) in contrast with others reporting no (6 -8 ) or only a little clinical impact (9 ). In a retrospective register-based study on 48250 patients, Eggers et al. (6 ) found no evidence for a better risk prediction using sex-specific 99th percentiles. Consistent with this, a substudy of TRAPID-AMI (High-sensitivity cardiac Troponin T assay for RAPID rule-out of Acute Myocardial Infarction) study on 1282 patients with suspected acute coronary syndrome (ACS) found no significant differences in outcome data when diagnoses were classified by sex-specific cutoffs (7 ). Cullen et al. (9 ) tested the performance of sex-specific cutoffs for prognostication of outcomes in an ACS population using the Abbott STAT hs-cTnI assay and found only marginal improvement of risk prediction. Interestingly, better outcome prediction was found at cutoffs substantially lower than the 99th percentile values (Ն6 ng/L for women and Ն7 ng/L for men using ROC analyses, a...

High-Sensitivity cardiac Troponins in Cardio-Healthy Subjects: A Cardiovascular Magnetic Resonance Imaging Study

“…However, the current clinical evidence supporting the use of sex-specific thresholds are controversial 30 – 33 . There are relevant concerns regarding the use of sex-specific thresholds 34 , 35 . It is also conceivable that the clinical decision limits for myocardial infarction in different assays are not biologically equivalent 36 .…”

Sex-specific, high-sensitivity cardiac troponin T cut-off concentrations for ruling out acute myocardial infarction with a single measurement

“…Previous work has shown that sex-specific cut-offs for ruling in MI increase classification performance by increasing the specificity of the assay. [7][8][9][10] We hypothesized, based on these findings, that similar improvements in classification performance would be observed for sexspecific, rule-out cut-off concentrations, with minimal loss of sensitivity. This would potentially enable more patients to have MI ruled out with a single hs-cTnT measurement compared to currently recommended universal rule-out cut-off concentrations.…”

“…6 Sex-specific diagnostic cut-offs for high-sensitivity troponin assays have been proposed for ruling-in MI. [7][8][9][10] In the rule-in scenario, sex-specific cut-offs improve diagnostic specificity and classification performance. [7][8][9][10] We hypothesized that sex-specific rule-out cut-offs would improve the classification performance of a single hs-cTnT measurement performed at ED arrival for rapidly ruling out MI with negligible loss of sensitivity.…”

Using single sex-specific high-sensitivity cardiac troponin cut-off values for ruling out myocardial infarction – Are we there yet?

“…As detailed in the counterpoint argument by Giannitsis, the adoption of ruling in MI with sex-specific cut off values in previous studies has shown very little clinical benefit. 9 The use of reclassification should be with caution due to inherent confirmation bias, as the troponin values are incorporated in the adjudication of MI outcome in these studies. Future studies are needed to confirm that sex-specific cut-offs improve the diagnosis of MI and specifically the impact on clinically important hard outcomes such as mortality, and revascularization procedures should be documented.…”