the sense of more sensitive troponin assays slides - the sense... · 2017. 2. 9. · history of...

The sense of more sensitive troponinassaysProf.dr.M.P. van Dieijen-Visser

2

History of cardiac markersSGOT/ASAT (Karmen)

LDH better performance

CK (Rosalki)

CK-MB activity (Sobel and Roberts)

CK-MB mass

Troponin T (Katus)

Troponin I (Ladenson)

Highly sensitive troponins

1954

1960

1967

1972

1986

1987

1992

Now:

Not specific

Highly specificHighly sensitive

Troponin 2.0

3

Spectrum of Acute Coronary Syndrome

Stable angina Unstable Angina Non-Q-wave MI Q-wave MI

Non-ST elevation ACS STE- MI

atherosclerosis

Plaque rupturepartial occlusion

complete occlusion

Troponin asprognostic biomarker

Troponin asdiagnostic biomarker

Troponin: The lower the better

4

Diagnosis of acute myocardial infarction

Clinical guidelines: Thygesen et al. Eur Heart J / JACC / Circulation 2007

Typical rise and/or fall of biomarkers, preferably troponin T or I,with at least 1 value above the 99th percentile reference limit

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

Analytical guidelines: Morrow et al. Clin Chem 2007

Cut-off

99%

www.bpac.org.nz

How well do we follow the guidelines?

CARMAGUE surveys 2006and 2010 from the EFCCworking group:

• More than 90% of thelaboratories use troponinas biomarker of first choice

• 70 % of the laboratories stillcombine troponin with othermarkers

Year

Numberhospitals

2006

220

2010

303

CK

(%)

87

(%)

59

AST 53 34

LDH 55 30

HBD 9.0 2.4

CK-MBactivity 38 8.3

CK-MBmass 31 21

Myoglobin 21 115

Do we use/know the right cut-off value or delta?6

ESC guidelinesEur Heart J 2011

D? Cut-off

7

High-sensitivity (hs) troponin assays

1990: cut-off 0.1 μg/L1995: 0.05 μg/L2004: 0.03 μg/L (10% CV) or <0.01 μg/L (99th percentile)2009: 0.014 μg/L = 14 ng/L (99th percentile)

Requirements

8

Assay requirementsAssay CV at 99th percentile <10%Assay CV <20% causes no misclassificationRatio troponin at 10% CV/ troponin at 99th percentile <1

Reference population requirementsSubjects included > 300Matched for age and gender

“cardio-healthy”: negative exercise-stress testand normal cardiac function measured by “non-invasive imaging”

Apple et al Clin Chem 2009

Cardiac troponin assay scorecard

9

Acceptance designation Total precision at 99th

percentileGuideline acceptable <10%Clinically usable >10 to £20%Not acceptable >20%Assay designation Measurable values below

the 99th percentileLevel 1 <50%Level 2 50 to < 75%Level 3 75 to < 95%Level 4 ≥ 95%

Website IFCC

10

AppleetalC

linC

hem2009

How consistent are these data?

11

Roche TnT : Assay performance

Assay level (% measurable data)

• Pre-commercial assay:– > 1ng/L 97% level 4

• Commercial Assay:– > 3 ng/L 62% level 2

12

Mingels et al. Clin Chem 2009Jacobs et al. ACB 2009

Guideline acceptable:

TnT at 10%CV / TnT at 99th

percentile:ratio 0.56

Percentage measurable concentrations13

Samples were frozen three times !

Level 1 <50%

Level 2 50 to < 75%

Level 3 75 to < 95%

Level 4 ≥ 95%

Level1

Apple et al. Clin Chem 58:1574-81 (2012)

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

14

15

Estimation of 99th percentile (URL)

Reference population requirements

Subjects included > 300

Matched for age and gender

“cardio-healthy”: negative exercise-stress testand normal cardiac function measured by “non-invasive imaging”

Limitations

Large cohort, difficult/expensive to fully screen, lessinfluence outliersSmall Cohort, more influence of outliers, screening

easier

CARMAGUE survey 2010: Where do laboratoriesget their information on decision limits,

• Most laboratories use 10%CV or 99th percentile

• >50% of labs use Data sheet,package insert

How correct are the datasheetvalues?

2010

10% CV99th percentileROC curveOther

2010

Data sheet

IFCC//NACB

ESC / ACC 2000

Universal definition

Peer-reviewedliteratureReference 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 oftroponin 99th percentiles.

• 40% of the studies included less than the required 300subjects

• 50% of the studies insufficiently reported exclusioncriteria

• No study met all criteria of “cardio-healthy” population

Cardinaels et al. CCLM 2012;50:791-806

Assays studied18

Assay RatioIFCC table

Roche hs-TnT 0.93 A level 2

ADVIA centaur TnI-Ultra (Siemens) 0.75 A level 1

Accu TnI (Beckman Coulter)Now improved

1.50 U level 21.00

Stratus CS Acute Care cTnI(Siemens)

0.86 A level 1

Vitros Eci cTnI ES (Ortho) 1.00 A level 1

Architect cTnI (Abbott)Now hs-TnI improved

1.14 U level 10.18

19

Roche hs-TnT: 99th percentile from 12 different studies

No informationMinor exclusionSome exclusionCareful exclusion cardiac disease

* ***

* Significant difference male/female

Guideline acceptable in 11studies (ratio<1)

Variation between studies 11%


------- Datasheet value

20

Roche Hs-TnT: Significant difference male-female

Study Numbersubjects

Male Female Ratiomale/female

Mingels2009

479 18 8 2.3

Giannitsis 2010

616 14.5 10 1.5

Saenger 533 15.5 8.9 1.7

Koerbin2010

104 12.9 11 1.2


21

Hs-TnI ADVIA Centaur : 99th percentile from 11 different studies

No informationMinor exclusionMore exclusionCareful exclusion cardiac disease

* *

*


* = Significant difference male/ femaleGuideline acceptable in 7 studies.



22

AccuTnI Access Beckman : 99th percentile 16 different studies

No selection/examinationMinor exclusionMore exclusionCareful exclusion cardiac disease

*

*


* = Significant difference male/ femaleGuideline acceptable in 4 studies.

*



Variation in 99th percentiles found in different studiesAssay Mean

99th %SD CV % IFCC

99th %Roche hs-TnT 14.5 1.61 11.1 14

ADVIA centaur TnI-Ultra(Siemens)

53.6 23.4 43.6 40

Accu TnI (BeckmanCoulter) *

39.7 19.0 47.9 40

Stratus CS Acute CarecTnI (Siemens)

60 20 33.3 70

Vitros Eci cTnI ES(Ortho)

25.0 10.5 42 34

Architect cTnI (Abbott)* 22.6 7.5 33.2 28

* improved methods recently introduced

Large variation in values found, especially for TnI

23

Guideline acceptability of assays24

Assay Mean Ratio10%CV /99th%

SD RatioIFCC table

Roche hs-TnT 0.86 0.19 0.92 A level 2

ADVIA centaur TnI-Ultra(Siemens)

1.03 0.62 0.75 A level 1

AccU TnI (Beckman Coulter)Now hs-TnI (ratio 1.0)

1.77 1.55 1.50 U level 2

Stratus CS Acute Care cTnI(Siemens)

1.24 0.63 0.86 A level 1

Vitros Eci cTnI ES (Ortho) 2.60 2.31 1.00 A level 1

Architect cTnI (Abbott)Architect hs-TnI pre-

commercial

1.880.18

1.22 1.11 U level 1A level 4

Large difference between mean obtained from different studies versus IFCC info

Continuous improvements: Abbott ARCHITECT pre-commercial

25

Datasheet: pre-commercial assayM 34.2 ng/LF 15.6 ng/LOverall 26.2 ng/LRatio 10% CV/ 99th % 0.18

Koerbin et alLevel 4 (98.6% measurable),guideline acceptableRatio 10% CV/ 99th % 0.29

Significant difference male/femaleOverall cut-off 13.6

Koerbin et al, Clin Chem Lab Med, 2012

male

female

26

D?ESC guidelinesEur Heart J 2011

Next Challenge….

Guidelines prescribe 20% Δ within 4-6 hours as basedon 3x SD of analytical variancesThygesen et al. JACC / Eur Heart J / Circulation 2007

• Reference change values

• Absolute delta values obtained from ROC-analysis

Serial troponin testing and use of Δ

Reference change values (%)

Assay RCV%

RCV+rise (%)

RCV-fall (%)

cTnI Beckman Coulter 45 64 -39 Apple, 2011

cTnI Beckman Coulter 45 -16 Vasile, 2011

hs-TnI Abbott Architect 49 54 -35 Nordenskjold, 2013

hs-TnT Roche Modular E170 47 64 -39 Frankenstein

hs-TnT Roche Modular E170 85 Vasile, 2011

hs-TnT Elecsys 23 26 -21 Nordenskjold, 2013

28

29

A rise or fall ? Change values obtainedfrom NSTEMI patients presenting at EDfor hs-cTnT D2 hours +7 ng/L Reichlin et al. Circulation 2011

D6 hours +9 ng/L Mueller et al. Clin Chem 2012

Reichlin et al. Circulation 2011

30

Conclusions• 99th % 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

Acknowledgements

• Eline Cardinaels• Alma Mingels• Steven Meex• Lieke Klinkenberg• Vincent Kleijnen

• EFCC working group on Cardiac MarkersLaitinen,P, Pulkki,K.; Suvisaari,J.; Collinson,P.;Ravkilde,J.; Stavljenic-Rukavina,A.; Hammerer-Lercher,A.; Baum,H.;

31

32

Voorbeeld van een afbeelding

the sense of more sensitive troponin assays slides - the sense... · 2017. 2. 9. · history of...

Documents