Clinical Biochemistry 48 (2015) 749–750

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Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem

Editorial

Sex-specific cutoffs for cardiac troponin using high-sensitivity assays — Is there clinical equipoise?

For nearly two decades, cardiac troponin (cTn) has been interpreted using one cutoff level for both female and male patients. In practice, the cutoff concentration has changed over this timeframe from a ROCderived cutoff, to an analytical imprecision cutoff to the 99th percentile [1,2]. However, the clinical definition for myocardial infarction (MI), since the 2000 redefinition has unequivocally endorsed the 99th percentile (upper reference limit derived from a healthy population) as the cutoff [3,4]. Of note, the Third Universal Definition of Myocardial Infarction in 2012 did state the following regarding high-sensitivity cardiac troponin (hs-cTn): “Sex-dependent values may be recommended for high-sensitivity troponin assays.” [4]. The “may be recommended” phrase captures the current practice for laboratories outside of the United States offering hs-cTn testing with some reporting one overall cutoff, others sex-specific cutoffs, with some laboratories using both sex-specific and overall cutoffs. Arguments have been brought forward in favor of sex-specific cutoffs [5,6]. Data is emerging in this area, but is there sufficient evidence for all hs-cTn assays to be interpreted with sex-specific cutoffs? In this issue of the Journal, the important observations reported by Eggers and colleagues provide yet another important piece in the sex/hs-cTn puzzle [7]. Using the Abbott ARCHITECT hs-cTnI assay in 70-year old men (n = 502) and women (n = 502) from the community and reported the predictive value of cTnI concentrations for cardiovascular events during long-term follow-up. Their analyses found that the interaction terms of sex on the associations of cTnI with outcomes were non-significant and that sex-specific cutoffs did not improve prognostication. This work corroborates and extends similar findings from a large cohort (n = 4695) of patients with non-ST-segment elevation acute coronary syndromes [8]. Also in this acute population, analyses using the same hs-cTnI assay, use of sex-specific cutoffs did not improve prognostic performance. Overall, these novel insights should encourage us to re-examine the evidence for sex-specific cutoffs for hs-cTn. What was the basis for suggesting sex-specific cutoff levels? For some, but not all, cTn assays differences in concentrations between healthy women and healthy men have been observed [9]. For some hs-cTn assays including the one examined by Eggers and colleagues the difference in the 99th percentile between the sexes was substantial, for others the difference was small [9]. For hs-cTn assays, with which healthy women were shown to have lower cTn blood concentrations as compared to men [10], the use of a sex-specific 99th-percentile could avoid under-diagnosis of acute myocardial infarction (AMI) in women. A recent analysis comparing the use of a hs-cTnI assay using a low (16 ng/L) sex-specific cutoff in women has identified a

high-risk group; however the final findings whether implementation of sex-specific cutoffs will improve outcomes has yet to be reported (NCT01852123) [11]. Obviously, additional analyses from high-quality diagnostic and prognostic studies are necessary to better quantify the possible net effects of using sex-specific cutoffs both in the community and acute hospitalized populations. Fortunately, such analyses are currently ongoing. While sex-specific cutoffs and sex-specific strategies could potentially help to detect women with very small AMIs, they might also yield an increase complexity of decision making in the emergency department (ED) (i.e., two cutoffs rather than one) as well as a detrimental effect in men (e.g. by possibly missing AMIs using the higher sex-specific 99th-percentile in men). Data from the ongoing analyses in the diagnostic studies will have to elucidate how many patients (women and men) present with cTn concentrations between the overall and the sex-specific 99th percentiles. As other variables such as age have been shown to have a much more profound effect on cTn blood concentrations as compared to sex, it is clear that the aspect of sex should not be looked at in isolation. This is further highlighted by the fact that sex did not emerge as an independent variable in the novel 0 h/1 h-algorithms for early rule-out and early rule-in of AMI [12–14]. These cutoffs are assay-specific, but identical for women and men. Overall, the situation for cTn is rather similar to that of B-type natriuretic peptide (BNP) and NT-proBNP [15]. BNP and NT-proBNP blood concentrations have multiple cofounders including sex and age. For the use of BNP and NT-proBNP in the ED there is overwhelming consensus that women and men should be managed using identical cutoff vales [15]. As studies continue to investigate the relationship of biological sex and hs-cTn concentrations, it will be interesting to gauge where the evidence falls on using sex-specific cutoffs in the community and acute hospital populations; as a case may be made at present for clinical equipoise in this area with respect to health outcomes.

Conflict of interest disclosures Professor Mueller has received research grants from the European Union, Swiss National Science Foundation and the Swiss Heart Foundation, the Cardiovascular Research Foundation Basel, Abbott, Astra Zeneca, BioMerieux, Brahms, Roche, Siemens, Singulex, Sphingotec, and the University Hospital Basel, as well as speakers/ consulting honoraria from Abbott, ALERE, Astra Zeneca, BG medicine, BioMerieux, Brahms, Cardiorentis, Novartis, Radiometer, Roche, Sanofi, Siemens, and Singulex.

http://dx.doi.org/10.1016/j.clinbiochem.2015.07.005 0009-9120/© 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

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Editorial

Dr. Kavsak has received grants/honorariums/consultant/advisor fees from Abbott Laboratories, Abbott Point of Care, Beckman Coulter, Ortho Clinical Diagnostics, Roche Diagnostics, and Siemens Healthcare Diagnostics with respect to cardiac troponin testing. References [1] A.H. Wu, R.H. Christenson, Analytical and assay issues for use of cardiac troponin testing for risk stratification in primary care, Clin. Biochem. 46 (2013) 969–978. [2] P.O. Collinson, M.P. van Dieijen-Visser, K. Pulkki, A. Hammerer-Lercher, J. Suvisaari, J. Ravkilde, et al., Evidence-based laboratory medicine: how well do laboratories follow recommendations and guidelines? The Cardiac Marker Guideline Uptake in Europe (CARMAGUE) study, Clin. Chem. 58 (1) (2012) 305–306. [3] J.S. Alpert, K. Thygesen, E. Antman, J.P. Bassand, Myocardial infarction redefined — a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction, J. Am. Coll. Cardiol. 36 (2000) 959–969. [4] K. Thygesen, J.S. Alpert, A.S. Jaffe, M.L. Simoons, B.R. Chaitman, H.D. White, Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction, Third universal definition of myocardial infarction, Circulation 126 (2012) 2020–2035. [5] A.S. Jaffe, F.S. Apple, High-sensitivity cardiac troponin assays: isn't it time for equality? Clin. Chem. 60 (2014) 7–9. [6] F.S. Apple, A.S. Jaffe, Men are different than women: it's true for cardiac troponin too, Clin. Biochem. 47 (2014) 867–868. [7] K.M. Eggers, N. Johnston, L. Lind, P. Venge, B. Lindahl, Cardiac troponin I levels in an elderly population from the community — the implications of sex, Clin. Biochem. 48 (2015) 751–756. [8] E.A. Bohula May, M.P. Bonaca, P. Jarolim, E.M. Antman, E. Braunwald, R.P. Giugliano, et al., Prognostic performance of a high-sensitivity cardiac troponin I assay in patients with non-ST-elevation acute coronary syndrome, Clin. Chem. 60 (2014) 158–164. [9] F.S. Apple, R. Ler, M.M. Murakami, Determination of 19 cardiac troponin I and T assay 99th percentile values from a common presumably healthy population, Clin. Chem. 58 (2012) 1574–1581. [10] F.S. Apple, A.S. Jaffe, P. Collinson, M. Mockel, J. Ordonez-Llanos, B. Lindahl, et al., IFCC educational materials on selected analytical and clinical applications of high sensitivity cardiac troponin assays, Clin. Biochem. 48 (2015) 201–203.

[11] A.S. Shah, M. Griffiths, K.K. Lee, D.A. McAllister, A.L. Hunter, A.V. Ferry, et al., High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study, BMJ 350 (2015) g7873. [12] T. Reichlin, C. Schindler, B. Drexler, R. Twerenbold, M. Reiter, C. Zellweger, et al., One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T, Arch. Intern. Med. 172 (2012) 1211–1218. [13] T. Reichlin, R. Twerenbold, K. Wildi, M.R. Gimenez, N. Bergsma, P. Haaf, et al., Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a high-sensitivity cardiac troponin T assay, CMAJ 187 (2015) E243–E252. [14] M. Rubini Gimenez, R. Twerenbold, C. Jaeger, C. Schindler, C. Puelacher, K. Wildi, et al., One-hour rule-in and rule-out of acute myocardial infarction using highsensitivity cardiac troponin I, Am. J. Med. (Mar 31 2015). http://dx.doi.org/10. 1016/j.amjmed.2015.01.046 (pii: S0002-9343(15)00256-9). [15] K. Thygesen, J. Mair, C. Mueller, K. Huber, M. Weber, M. Plebani, et al., Recommendations for the use of natriuretic peptides in acute cardiac care: a position statement from the Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care, Eur. Heart J. 33 (Aug 2012) 2001–2006.

Christian Mueller Department of Cardiology and Cardiovascular Research Institute Basel (CRIB), University Hospital Basel, Switzerland Corresponding author at: Department of Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail address: [email protected]. Peter A. Kavsak Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON Canada

Sex-specific cutoffs for cardiac troponin using high-sensitivity assays--Is there clinical equipoise?

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