The sense of more sensitive troponin assays Prof.dr.M.P. van - PowerPoint PPT Presentation

The sense of more sensitive troponin assays Prof.dr.M.P. van Dieijen-Visser

2 History of cardiac markers 1954 SGOT/ASAT (Karmen) Not specific 1960 LDH better performance 1967 CK (Rosalki) 1972 CK-MB activity (Sobel and Roberts) 1986 CK-MB mass 1987 Troponin T (Katus) 1992 Troponin I (Ladenson) Highly specific Highly sensitive Now: Highly sensitive troponins Troponin 2.0

3 Spectrum of Acute Coronary Syndrome Stable angina Unstable Angina Non-Q-wave MI Q-wave MI Troponin as Troponin as prognostic biomarker diagnostic biomarker Non-ST elevation ACS STE- MI complete occlusion partial occlusion Plaque rupture atherosclerosis Troponin: The lower the better

4 Diagnosis of acute myocardial infarction C ut-off Typical rise and/or fall of biomarkers, preferably troponin T or I, with at least 1 value above the 99 th percentile reference limit 99% With at least one of the following: • Ischemic symptoms • ECG changes (ST-T changes, pathological Q waves) • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality Clinical guidelines: Thygesen et al. Eur Heart J / JACC / Circulation 2007 Analytical guidelines: Morrow et al. Clin Chem 2007 www.bpac.org.nz

How well do we follow the guidelines? Year 2006 2010 CARMAGUE surveys 2006 and 2010 from the EFCC Number 220 303 working group: hospitals (%) (%) • More than 90% of the CK 87 59 laboratories use troponin AST 53 34 as biomarker of first choice LDH 55 30 HBD 9.0 2.4 • 70 % of the laboratories still CK-MBactivity 38 8.3 combine troponin with other markers CK-MBmass 31 21 Myoglobin 21 11 5

6 Do we use/know the right cut-off value or delta? D ? Cut-off ESC guidelines Eur Heart J 2011

7 High-sensitivity (hs) troponin assays 1990: cut-off 0.1 μ g/L 0.05 μ g/L 1995: 0.03 μ g/L (10% CV) or <0.01 μ g/L (99th percentile) 2004: 0.014 μ g/L = 14 ng/L (99th percentile) 2009:

8 Requirements Assay requirements Assay CV at 99 th percentile <10% Assay CV <20% causes no misclassification Ratio troponin at 10% CV/ troponin at 99 th percentile <1 Reference population requirements Subjects included > 300 Matched for age and gender “cardio-healthy”: negative exercise-stress test and normal cardiac function measured by “non- invasive imaging” Apple et al Clin Chem 2009

9 Cardiac troponin assay scorecard Acceptance designation Total precision at 99 th percentile Guideline acceptable <10% >10 to £ 20% Clinically usable Not acceptable >20% Assay designation Measurable values below the 99 th percentile Level 1 <50% Level 2 50 to < 75% Level 3 75 to < 95% ≥ 95% Level 4 Website IFCC

10 Apple et al Clin Chem 2009

11 How consistent are these data?

12 Roche TnT : Assay performance Guideline acceptable: TnT at 10%CV / TnT at 99 th percentile: ratio 0.56 Assay level (% measurable data) • Pre-commercial assay: – > 1ng/L 97% level 4 • Commercial Assay: – > 3 ng/L 62% level 2 Mingels et al. Clin Chem 2009 Jacobs et al. ACB 2009

13 Percentage measurable concentrations Level1 Level 1 <50% Level 2 50 to < 75% Level 3 75 to < 95% ≥ 95% Level 4 Samples were frozen three times ! Apple et al. Clin Chem 58:1574-81 (2012)

14 Roche hs-TnT “Slight” down-shift of 6 lot numbers

15 Estimation of 99 th percentile (URL) Reference population requirements Subjects included > 300 Matched for age and gender “cardio-healthy”: negative exercise-stress test and normal cardiac function measured by “non- invasive imaging” Limitations Large cohort, difficult/expensive to fully screen, less influence outliers Small Cohort, more influence of outliers, screening easier

CARMAGUE survey 2010: Where do laboratories get their information on decision limits, 2010 10% CV 99th percentile • Most laboratories use 10% ROC curve CV or 99 th percentile Other • >50% of labs use Data sheet, 2010 package insert Data sheet IFCC//NACB ESC / ACC 2000 How correct are the datasheet Universal definition values? Peer-reviewed literature Reference limits Locally derived Clin Chem Lab Med 2009;47:227-34. Clin Chem. 2012;58:305-6.

17 Review of 44 papers, 6 methods on estimation of troponin 99 th percentiles. • 40% of the studies included less than the required 300 subjects • 50% of the studies insufficiently reported exclusion criteria • No study met all criteria of “cardio-healthy” population Cardinaels et al. CCLM 2012;50:791-806

18 Assays studied Assay Ratio IFCC table Roche hs-TnT 0.93 A level 2 ADVIA centaur TnI-Ultra (Siemens) 0.75 A level 1 Accu TnI (Beckman Coulter) 1.50 U level 2 Now improved 1.00 Stratus CS Acute Care cTnI 0.86 A level 1 (Siemens) Vitros Eci cTnI ES (Ortho) 1.00 A level 1 Architect cTnI (Abbott) 1.14 U level 1 Now hs-TnI improved 0.18

19 Roche hs-TnT: 99 th percentile from 12 different studies No information * * Minor exclusion * * Some exclusion Careful exclusion cardiac disease ------- Datasheet value * Significant difference male/ female Guideline acceptable in 11 studies (ratio<1) Variation between studies 11% Cardinaels et al. CCLM 2012;50:791-806

20 Roche Hs-TnT: Significant difference male-female Study Number Male Female Ratio subjects male/ female Mingels 479 18 8 2.3 2009 Giannitsi 616 14.5 10 1.5 s 2010 Saenger 533 15.5 8.9 1.7 Koerbin 104 12.9 11 1.2 2010 Cardinaels et al. CCLM 2012;50:791-806

21 Hs-TnI ADVIA Centaur : 99 th percentile from 11 different studies No information * * Minor exclusion More exclusion Careful exclusion cardiac disease * ------- Datasheet value Variation between studies 44% * = Significant difference male/ female Guideline acceptable in 7 studies. Cardinaels et al. CCLM 2012;50:791-806

22 AccuTnI Access Beckman : 99 th percentile 16 different studies * No selection/examination Minor exclusion * More exclusion * Careful exclusion cardiac disease ------- Datasheet value Variation between studies 48% * = Significant difference male/ female Guideline acceptable in 4 studies. Cardinaels et al. CCLM 2012;50:791-806

23 Variation in 99 th percentiles found in different studies Assay Mean SD CV % IFCC 99 th % 99 th % Roche hs-TnT 14.5 1.61 11.1 14 ADVIA centaur TnI-Ultra 53.6 23.4 43.6 40 (Siemens) Accu TnI (Beckman 39.7 19.0 47.9 40 Coulter) * Stratus CS Acute Care 60 20 33.3 70 cTnI (Siemens) Vitros Eci cTnI ES 25.0 10.5 42 34 (Ortho) Architect cTnI (Abbott)* 22.6 7.5 33.2 28 * improved methods recently introduced Large variation in values found, especially for TnI

24 Guideline acceptability of assays Assay Mean Ratio SD Ratio 10%CV / IFCC table 99th% Roche hs-TnT 0.86 0.19 0.92 A level 2 ADVIA centaur TnI-Ultra 1.03 0.62 0.75 A level 1 (Siemens) AccU TnI (Beckman Coulter) 1.77 1.55 1.50 U level 2 Now hs-TnI (ratio 1.0) Stratus CS Acute Care cTnI 1.24 0.63 0.86 A level 1 (Siemens) Vitros Eci cTnI ES (Ortho) 2.60 2.31 1.00 A level 1 Architect cTnI (Abbott) 1.88 1.22 1.11 U level 1 Architect hs-TnI pre- 0.18 A level 4 commercial Large difference between mean obtained from different studies versus IFCC info

25 Continuous improvements: Abbott ARCHITECT pre-commercial male Datasheet: pre-commercial assay M 34.2 ng/L F 15.6 ng/L Overall 26.2 ng/L Ratio 10% CV/ 99 th % 0.18 Koerbin et al female Level 4 (98.6% measurable), guideline acceptable Ratio 10% CV/ 99 th % 0.29 Significant difference male/female Overall cut-off 13.6 Koerbin et al, Clin Chem Lab Med, 2012

26 Next Challenge…. D ? ESC guidelines Eur Heart J 2011

Serial troponin testing and use of Δ Guidelines prescribe 20% Δ within 4-6 hours as based on 3x SD of analytical variances Thygesen et al. JACC / Eur Heart J / Circulation 2007 • Reference change values • Absolute delta values obtained from ROC-analysis

28 Reference change values (%) Assay RCV RCV+ RCV- % rise (%) fall (%) Apple, 2011 cTnI Beckman Coulter 45 64 -39 Vasile, 2011 cTnI Beckman Coulter 45 -16 hs-TnI Abbott Architect Nordenskjold, 2013 49 54 -35 hs-TnT Roche Modular E170 Frankenstein 47 64 -39 Vasile, 2011 hs-TnT Roche Modular E170 85 Nordenskjold, 2013 hs-TnT Elecsys 23 26 -21

29 A rise or fall ? Change values obtained from NSTEMI patients presenting at ED D 2 hours +7 ng/L Reichlin et al. Circulation 2011 for hs-cTnT D 6 hours +9 ng/L Mueller et al. Clin Chem 2012 Reichlin et al. Circulation 2011

30 Conclusions • 99 th % strongly dependent on reference population • Large cohort (>1000): lower values • Strong exclusion criteria for cardiac disease: lower values. • Larger variations for Troponin I. • Difference between male and female – TnT ~1.7 times higher in males – TnI ~ 1.2 times higher in males • Higher values in elder population • Uncertainty about cut-off values complicates diagnostics • Package insert data very important • Estimation of D cTn for each assay