Är dagens troponinmetoder tillräckligt känsliga?

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1 Är dagens troponinmetoder tillräckligt känsliga? Per Venge, MD PhD Professor Department of Medical Sciences Uppsala University and Department of Clinical Chemistry and Pharmacology University Hospital Uppsala Sweden

2 The clinical utility of high sensitive cardiac troponin assays Diagnosis of myocardial injury myocardial infarction Outcome prediction death/ami

3 FRISC-1 % 20 Probability of cardiac death TnT 0.60 g/l p=0.007 TnT g/l 10 p= Lindahl B et al,nejm TnT <0.06 g/l 54 Months

4 20 FRISC-II invasive study - death/ami (%) AccuTnI Non-invasive / TnI 0.02 g/l RR (95 % CI) 0.70 ( ) p= Invasive / TnI 0.02 g/l Invasive / TnI <0.02 g/l Non-invasive / TnI <0.02 g/l p=ns Days

5 Acute coronary syndrome - diagnosis and prediction o AMI rule out: Troponin <99 th or >99 th percentile URL, but no symptoms or signs of ischemia AMI rule in: Symptoms and/or signs of ischemia with Troponin >99th percentile or >10% CV cut-off and rise and/or fall Outcome prediction Increased risk: Troponin >99 th percentile No increased risk: Troponin <99 th percentile

6 What is normal? The 99 th percentile how should it be defined? Dependent on: Assay Reference cohort

7 ctni, AccuTnI in a healthy reference population n=436 (SWISCH) 0,08 0,07 0,06 ctni, AccuTnI g/l 0,05 0,04 0,03 0,02 99 th percentile URL 99 th percentile <60 y 0,01 0, Age

8 Prediction of Death/AMI by the ctni AccuTnI assay (FRISC II) p=0.004 p< % Death/AMI < >0.039 ctni AccuTnI, g/l

9 Outcome (Death) in 70 years old men, with or without CVD, in relation to ctroponin I (AccuTnI) 80 p< p< Outcome. death % 40 p=0.002 p= >0.039 >0.02-<0.04 <0.021 >0.039 >0.02-<0.04 <0.021 Healthy Diseased ctroponin I, g/l

10 What characterizes 70-year old men with minor elevations of cardiac troponin I? Blood-Glucose Oral Glucose Tolerance Test (OGTT) Plasma-Insulin Insulin Sensitivity Index Intact Proinsulin Serum Triglycerides Serum Cholesterol HDL Cholesterol LDL Cholesterol HDL/LDL ratio Apolipoprotein A1 Apolipoprotein B ApoA1/ApoB Body mass index (BMI) Waist circumference Hip circumference NT-proBNP Cystatin C CRP Urine Albumin Smoking Blood Pressure

11 NT-proBNP in relation to ctni in 70-year old men (ULSAM) Serum NT-proBNP in relation to ctni in 70-year old men NT-proBNP in relation to ctni in seemingly healthy 70-year old men g/l p<< (ANOVA) g/l p<< (ANOVA) Serum NT-proBNP, < >0.039 ctni, g/l Serum NT-proBNP, < >0.039 ctni, g/l

12 Prediction of 5-year mortality in participants from the FRISC II-study by cardiac troponin I (AccuTnI) levels at 6 months by applying different cut offs Clinical Chemistry 55:1 (2009)

13 Frequency ctni, g/l Access ctni prototype assay 160 High-sensitive ctni, Access in a healthy reference population (n=542) 1 High- sensitive ctni, Access in a healthy reference population (n=542) ctni, g/l Men (n=319) Women (n=213)

14 ctni, g/l The 99 th and 97.5 th percentiles of ctni, Access in the reference populations below or above 60 years of age after exclusion of outliers High sensitive ctni, Access in a healthy reference population below 60 years of age High sensitive ctni, Access in a healthy reference population above 60 years of age th percentile th percentile 97.5 th percentile th percentile Men Women Men Women 97.5 th percentile : g/l 99 th percentile : g/l 97.5 th percentile : g/l 99 th percentile : g/l Outliers = >0.012 g/l Outliers = >0.028 g/l

15 ctni, g/l Cardiac troponin I levels in patients with unstable angina and NSTEMI as compared to healthy references (9 hours) 10 1 P< Healthy Controls GUSTO IV-patients ctnt <0.03 g/l GUSTO IV-patients ctnt 0.03 g/l Unstable Angina NSTEMI

16 Sensitivity Sensitivity Discrimination between healthy subjects and GUSTO IV patients with ACS and ctnt below or above 0.03 µg/l Sensitivity: 98.7 Specificity: 96.3 Cut-off: g/l Sensitivity: Specificity: 76.0 Cut-off: g/l Specificity Specificity GUSTO IV-patients with ctnt <0.03 g/l GUSTO IV-patients with ctnt 0.03 g/l

17 ctni, g/l Cardiac troponin I levels in patients with unstable angina and NSTEMI as compared to healthy references (9 hours). One year mortality in relation to cut-offs 10 1 P< Cut-off %/2.8%, p<0.001 Cut-off %/0%, Ns Healthy Controls GUSTO IV-patients ctnt <0.03 g/l GUSTO IV-patients ctnt 0.03 g/l Unstable Angina NSTEMI

18 Frequency frequency High sensitive Troponin T assay. Reference levels Reference Study MCE TnT hs, n = Uppsala cohort ,000 0,003 0,006 0,009 0,012 0,015 0,018 0,021 0,024 Troponin T hs ng/ml Troponin T hs [pg/ml]

19 Troponin T hs [ng/ml] The Troponin T levels are related to gender and age Reference Study Elecsys TnT hs m m m m m >60 f f f f f >60 Age Group [years]

20 Hs-TnT, ng/l High sensitive cardiac troponin T in the GUSTOIV cohort (48h) th perc URL 1 0,1 0,01 Healthy Controls GUSTO IV-patients ctnt <0.03 g/l Unstable Angina GUSTO IV-patients ctnt 0.03 g/l NSTEMI

21 Mortality at 1 year, death or AMI at 30 days, and PCI at 30 days in patients in relation to hs-ctnt and ctnt levels Neg/Neg Pos/Neg Pos/Pos

22 A comparison of analytical and clinical performances of five cardiac troponin assays Consecutive study on 1069 patients admitted to the emergency room Laboratory assays: Access AccuTnI and Architect ctni POCT assays: Biosite Triage, i-stat and Stratus CS

23 Access AccuTnI i-stat Stratus CS Biosite Triage Access AccuTnI i-stat Stratus CS Biosite Triage = *Architect = *Architect = *Architect = *Architect ctni, g/l ctni, g/l Architect ctni, g/l Architect ctni, g/l

24 th percentiles i-stat ctni, g/l th percentile Access AccuTnI ctni, g/l

25 The proportion of patients above clinical cut-offs for AMI (99th percentiles URL or 10%CV) a comparison between five ctni assays Cut-off (99th percentile URL or 10% CV) Access g/l 74% Access g/l 48 % Architect g/l 39 % Stratus CS 0.07 g/l 27 % *** Patients with results above cut-offs, % i-stat 0.08 g/l 20 %***, Biosite Triage 0.05 g/l 15 %***, Laboratory Assays vs POC assays: p<0.001 (***) Stratus CS vs other two POC assays: p=0.03 ( ), p<0.001 ( )

26 Per cent deaths The percentage of patients who died within 35 months after admission with elevated ctni levels >99 th percentile URLs of four ctni assays 100 All cause deaths CVD deaths p<0.001 p< Access AccuTnI Architect ctni Stratus CS ctni i-stat ctni Access AccuTnI Architect ctni Stratus CS ctni i-stat ctni

27 Prediction of CVD deaths by i-stat ctni and Stratus CS ctni in comparison with Architect TnI and Access AccuTnI Architect Architect Access Access Access Access < < < g/l g/l g/l g/l g/l g/l i-stat <0.08 g/l 17(21%) 23(28%) 10(12%) 33(38%) 2(2%) 41(48%) i-stat 0.08 g/l 0 41(51%) 0 43(50%) 0 43(50%) Stratus CS <0.07 g/l Stratus CS 0.07 g/l 17(19 %) 24(26 %) 12 (15 %) 32 (33%) 3(3 %) 41 (43 %) 0 50(55 %) 1(1 %) 51(53 %) 0 52 (54 %) The laboratory assays predict significantly more patients with a poor prognosis as to death in CVD than the POC assays (p<0.0001)

28 How sensitive should a cardiac troponin assay be? Sensitive enough to identify all subjects at risk of premature death in CVD This requires: Assays that measure normal levels of cardiac troponins with acceptable imprecision The currently available POC assays are too insensitive for risk prediction. Negative results should always be confirmed by sensitive laboratory assays

29 It is not only sensitivity that matters the assay must pick up the clinically relevant molecules! A comparison between Access AccuTnI and Siemens Centaur ctni Ultra

30 Centaur ctni AccuTnI AccuTnI, ug/l

31 0,16 ctni (Centaur) in a healthy reference population (SWISCH) 0,14 0,12 Centaur ctni, g/l 0,10 0,08 0,06 0,04 99 th percentile (3 outliers excluded) 99th percentile <60 years 0,02 0, Age, years

32 AccuTnI is superior in clinical performance to Centaur TnI Ultra 10 % CV cut-offs ctni Centaur <0.03 µg/l AccuTnI <0.014 µg/l 32 (2.5%) Death 0 DMI 0 AccuTnI µg/l 255 (20.4%) Death 13 (5.1%) AccuTnI vs Centaur ctni: Concordance DMI 6 (2.4%) ctni Centaur < th percentile cut-offs µg/l (SWISCH defined) AccuTnI <0.04 µg/l 285 (22.8%) Death 15 (5.3%) DMI 6 (2.1%) AccuTnI 0.04 µg/l 133 (10.6%) Death 12 (9.0%) AccuTnI vs Centaur ctni: Concordance DMI 7 (5.3%) ctni Centaur 0.03 µg/l 3 (0.2%) Death 0 DMI (76.8%) Death 95 (9.9%) 79.3% DMI 87 (9%) ctni Centaur 0.08 µg/l 7 (0.6%) Death 1 DMI (66.1%) Death 80 (9.7%) 88.9% DMI 79 (9.6%) Differences in proportions of deaths within one year (D) or Death and/or MI within 30 days (DMI) (McNemar s test) p= (D) p=0.03 (DMI) p=0.003 (D) p=0.07 (DMI)

33 Clinical performances of AccuTnI and Centaur ctni 99 th percentiles URL <60 years ctni Centaur <0.03 µg/l AccuTnI <0.02µg/L 89 (7.1%) Death 3 AccuTnI 0.02 µg/l 199 (15.8%) Death 10 (5.0%) ctni Centaur 0.03 µg/l 8 (0.6%) Death (76.5%) Death 82 (8.5%) AccuTnI identified significantly more patients at risk; p<0.001

34 Cardiac Troponin I Regions subject to auto-antibody formation N-terminal Cardiac Specific Region Most Stable Region C-terminal aa Phosphorylation Ser-23, Ser-24 Oxidization Cys-80, Cys-97 Heparin Interference AccuTnI Binding Regions Centaur TnI-Ultra

35 Cardiac Troponin assays - Requirements High sensitivity that allows the measurements of normal levels High specificity that allows the measurement of the relevant molecules

36 Biochemical diagnosis and prediction in cardio-vascular disease FABP Choline Myocardium (ctroponins) IMA PAPP-A Homeostasis (Creatinine, Cystatin C, BNP) GDF-15 Metabolism (Diabetes, oxldl, lipids, homocysteine) Coagulation Inflammation (hs-crp, IL-6, MPO) PlGF (Fibrinogen and more) CD40L

37 Relations of established risk markers to cardiovascular mortality in 70-year old men without CVD at baseline. Unadjusted 5 4 Hazard Ratio 3 HDL-Cholesterol Lipid lowering treatment Total cholesterol BMI Systolic BP Age Anti-hypertensive treatment Diabetes Cystatin C >1.29 mg/l Smoking CRP>3.0 mg/l Troponin I >0.021 ug/l NT-proBNP >386 ng/l 2 1 0

38 The Prediction of Cardiovascular Mortality by Combinations of different Biomarkers with Troponin I ULSAM-study (Whole cohort n=1135) Troponin I/CRP/Cystatin C/NT-proBNP Troponin I/Cystatin C/NT-proBNP Troponin I/CRP/NT-pro-BNP Troponin I/CRP/Cystatin C Troponin I/NT-proBNP Troponin I/Cystatin C Troponin I/CRP Troponin I Hazard Ratio All models are adjusted for established risk factors and significantly different from the referent (p<0.001) NEJM May 2008 Cut-off points: CRP 3 mg/l, Cystatin C 1.29 mg/l, NT-proBNP 386 ng/l Troponin I g/l

39 Collaborators Bertil Lindahl Lars Wallentin Erik Diderholm Stefan James Tomas Jernberg Nina Johnston Kai Eggers Several others at the Cardiology Department, Uppsala The FRISC II Study group ULSAM Study group Björn Zethelius PIVUS study group Lars Lind The laboratory staff at the Department of Clinical Chemistry, Uppsala

Troponin Assessment. Does it Carry Clinical Message? Stefan Blankenberg. University Heart Center Hamburg

Troponin Assessment. Does it Carry Clinical Message? Stefan Blankenberg. University Heart Center Hamburg Biomarkers for Optimal Management of Heart Failure Troponin Assessment Does it Carry Clinical Message? Stefan Blankenberg University Heart Center Hamburg Congress of the European Society of Cardiology