Sex-specific versus overall cut points for a high sensitivity troponin I assay in predicting 1-year outcomes in emergency patients presenting with chest pain

Cullen, Louise; Greenslade, Jaimi; Carlton, Edward; Than, Martin; Pickering, John W.; Ho, Ariel; Greaves, Kim; Berndt, Sara; Body, Richard; Ryan, Kimberley; Parsonage, William

doi:10.1136/heartjnl-2015-308506

Cited by 67 publications

(38 citation statements)

References 18 publications

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“…Regarding the highly sensitive cTnI assay, some studies report that the use of gender specific decision values significantly increases AMI diagnosis especially in women, with better stratification of risk [112,[135][136][137], while another study found contradictory results [138]. The evidences regarding the highly sensitive cTnT assay are, on the contrary, all negative, suggesting that genderspecific clinical decision values are not particularly useful for the highly sensitive cTnT assay [117,118,139].…”

Section: Clinical Relevance Of Gender-specific Decision Values For Ctmentioning

confidence: 86%

The 99th percentile of reference population for cTnI and cTnT assay: methodology, pathophysiology and clinical implications

Clerico

Zaninotto

Ripoli

et al. 2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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According to recent international guidelines, including the 2012 Third Universal Definiton of Myocardial Infarction by the Joint ESC/ACCF/AHA/WHF Task Force, an increase in cardiac troponin (cTn) levels over the 99th percentile upper reference limit (99th URL) should be considered clinically relevant, this cut-off being measured with an imprecision ≤10 CV%. In theory 99th URL values strongly depend not only on demographic and physiological variables (i.e. criteria for considering the reference population "healthy"), but also on the analytical performance of cTn methods and mathematical algorithms used for the calculation. The aim of the present article was therefore to review the methodological and pathophysiological factors affecting the evaluation and calculation of the 99th URL for cTn assay. The critical analysis made showed that no uniform procedure is followed, and nor have experts or regulatory bodies provided uniform guidelines for researchers or cTn assays manufacturers as an aid in "their quest to define normality". In particular, little attention has been paid to the way in which a healthy reference population is to be selected, or the criteria for calculating the 99th URL value for cTn assays, thus highlighting the need for international recommendations not only for demographic and physiological variables criteria for defining a healthy reference population, but also for calculating mathematical algorithms for establishing/ calculating clinical decision values. An expert consensus group, comprising laboratory and clinical scientists, biomedical statisticians, industrial and regulatory representatives, should be responsible for drawing up these guidelines.

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Section: Clinical Relevance Of Gender-specific Decision Values For Ctmentioning

confidence: 86%

The 99th percentile of reference population for cTnI and cTnT assay: methodology, pathophysiology and clinical implications

Clerico

Zaninotto

Ripoli

et al. 2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…Shah et al (11 ) argue that the use of a single diagnostic threshold has disproportionately disadvantaged women and contributed to underdiagnosis of female AMI. Cullen and colleagues have recently shown that sex-specific cutoffs improve the identification of major cardiovascular event outcomes in women at 1 year (14 ). Our data show that there was no follow-on effect from increased cardiac troponin to angiography rates.…”

Section: Discussionmentioning

confidence: 43%

Impact of High-Sensitivity Troponin I Testing with Sex-Specific Cutoffs on the Diagnosis of Acute Myocardial Infarction

et al. 2016

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BACKGROUND: High-sensitivity cardiac troponin I (hscTnI) assays show sex-dependent differences in the 99th percentile of healthy populations, with concentrations in women approximately 50% lower. The adoption of sex-specific cutoffs seems appropriate, although it is not yet clear what effect these will have on acute myocardial infarction (AMI) diagnosis and management. METHODS:We conducted a retrospective pre-and postchangeover analysis of troponin I testing in the 6 months before and after moving from the contemporary Abbott Architect TnI assay (cTnI) to hs-cTnI at 2 tertiary centers in Australia and New Zealand. The cTnI cutoff was 30 ng/L for both sexes, whereas a female-specific cutoff of 16 ng/L was adopted upon changeover to hsTnI. RESULTS:Changeover from the cTnI assay to the hs-cTnI assay increased the number of female patients with increased troponin I concentrations at both sites (from 29.7% to 34.9% and from 22.4% to 30.8%; P Ͻ 0.001). There was no statistically significant change in the number of men with increased concentrations in the same time period (P ϭ 0.09). The increased percentage of women with increased troponin I was not associated with an increase in the number of women with AMI diagnoses at either center. Angiographic data available from 1 center showed no change in the percentage of angiograms performed in women. CONCLUSIONS:Although increasing the proportion of women with increased troponin I, adopting sex-specific cutoffs with the hs-cTnI assay did not lead to an increase in AMI diagnoses in females, or in the number of women undergoing angiography. © 2016 American Association for Clinical ChemistryCardiac troponins are the preferred biomarkers for the detection of myocardial injury, and a rise and/or fall above the 99th percentile is an integral part of the universal consensus definition for diagnosis of acute myocardial infarction (AMI) 8 (1 ). In recent years, technical improvements have led to the development of highsensitivity assays that are capable of measuring low concentrations of cardiac troponin with high precision. With such assays, we are now able to measure cardiac troponin in the serum of healthy individuals, including children, who have no evidence of cardiovascular disease (2-4 ). The advent of high-sensitivity assays has uncovered sexspecific differences in circulating cardiac troponin concentrations that were formerly unrecognized because previous assays could not measure cardiac troponin with sufficient precision at or below the 99th percentile. It is now clear that the 99th percentile is substantially lower in females than it is in males (2,(5)(6)(7). Accordingly, several laboratories have implemented sex-specific reference intervals for cTnI, although the clinical impact is as yet unclear.The revelation of sex-dependent differences in circulating cardiac troponin raises several questions regarding the interpretation of cardiac troponin in women, and its possible downstream clinical effects. These are particularly pertinent given the large body of evidence suggest...

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“…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.…”

mentioning

confidence: 92%

“…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, and Ն6 ng/L for women and Ն9 ng/L for men using logistic regression modeling). Therefore, Cullen et al (9 ) recommended consideration of lowering the clinical cutoff for both sexes for prognostic purposes instead of using sexspecific 99th percentile values as recommended by the manufacturer. Consistent with this, the optimal cutoffs for a rapid 1-h NSTEMI rule-out and rule-in algorithm in suspected ACS were determined as Ͻ5 and Յ6 ng/L, respectively with the use of the same STAT Architect hs-cTnI assay in 2 other large ACS cohorts (10 ).…”

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confidence: 99%

“…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, and Ն6 ng/L for women and Ն9 ng/L for men using logistic regression modeling).…”

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confidence: 99%

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

Giannitsis

2017

Clinical Chemistry

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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...

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Sex-specific versus overall cut points for a high sensitivity troponin I assay in predicting 1-year outcomes in emergency patients presenting with chest pain

Abstract: ISRCTN No. 21109279, ACTRN12609000283279.

Cited by 67 publications

References 18 publications

The 99th percentile of reference population for cTnI and cTnT assay: methodology, pathophysiology and clinical implications

The 99th percentile of reference population for cTnI and cTnT assay: methodology, pathophysiology and clinical implications

Impact of High-Sensitivity Troponin I Testing with Sex-Specific Cutoffs on the Diagnosis of Acute Myocardial Infarction

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

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