Point: The Use of Sex-Specific Cutpoints for High-Sensitivity Cardiac Troponin Assays

Abstract

Sex-specific reference intervals for cardiac troponin exist, with the 99th percentile (the cutpoint for determination of an increased troponin) being substantially lower in females than males (1,2 ). Although recent guidelines have recommended their use (3, 4 ), clinical utilization of sex-specific ranges is limited. Troponin is engrained in our assessment of risk, diagnosis of disease, treatment options, and determination of prognosis (5 ). Irrespective of sex, the risk of acute myocardial infarction (AMI), 3 cardiovascular death, recurrent MI, refractory ischemia, and rehospitalization increases with increasing troponin concentrations. The finding of an increased troponin often leads to targeted medical interventions designed to improve outcomes. The definition of an increased troponin is critical; if the cutpoint is set too high, there is the potential for missed diagnoses, leading to fewer receiving guideline-recommended management, and poorer outcomes. Currently women with acute coronary syndromes (ACS) receive less guideline-recommended treatment and have worse outcomes than men (6 ). Improved Risk Assessment, Diagnosis, and Determination of PrognosisMany assume that men have higher rates of MI compared with women. This is not supported by WHO statistics that report the proportion of men and women dying from coronary heart disease (CHD) in Europe are identical at 20% and 22% respectively (7 ). It is postulated that in the acute setting fewer women are evaluated for CHD owing to atypical symptoms and fewer electrocardiogram abnormalities than men (8 ). However, given troponin is integral to the diagnosis of AMI (4 ), it may also be that sex-specific differences in troponin cutoffs have contributed to differences in diagnostic rates. Women are known to have lower cardiac troponin values than men for any given extent of coronary artery disease (9 ) and this may result in fewer women being identified as high risk.Indeed, Shah et al. (10 ) investigated 1126 consecutive patients with suspected ACS. Clinical care was guided by a sensitive assay with a single diagnostic threshold (50 ng/L), but troponin concentrations were determined in parallel using a high-sensitivity (hs) assay. Cardiologists adjudicated the diagnosis of MI separately using the clinical assay and hs-troponin I assay with sexspecific cutpoints. Use of sex-specific thresholds doubled the rate of diagnosis in females (11% to 22%), but had minimal effect on males (19% to 21%). Although overall more men were diagnosed with MI, the proportion of both sexes with MI was comparable when sex-specific thresholds were applied. Women with small increases in troponin concentration, only detectable using the sexspecific threshold, had rates of death or reinfarction that were comparable to or worse than women with much larger infarcts identified using the clinical assay. However, the use of a higher clinical threshold may have magnified the impact of using sex-specific values. The inclusion of consecutive patients in this study avoids selection bias and indica...

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.…”

Establishing the 99th percentile for high sensitivity cardiac troponin I in healthy blood donors from Southern Italy

“…Although several reports documented a higher diagnostic accuracy of hs-cTnI when sex-specific cut-offs are used; the clinical consequences in terms of cardiovascular outcomes and mortality of using a unique hsTnI cut-off assessed by SMC technology haven’t been addressed yet ( 9 ). Thus, the clinical evaluation of a sex-specific hs-cTnI cut-off in comparison to a unique one is mandatory when this assay is used.…”