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

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1 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 Paris, August 27 th, 2011

2 DECLARATION OF CONFLICT OF INTEREST none

3 Use of Biomarkers

4 Cardiac troponin Cardiac Troponin I/T

5 Cardiac troponin Cardiac troponin and heart failure Cardiac troponin and intermediate phenotypes of heart failure Sensitive cardiac troponin and how to differentiate between early myocardial infarction and extracoronary sources like heart failure Highly sensitve cardiac troponin in the population

6 Keller et al., Circulation 2011

7 Troponin Assays Assay LoD µg/l 99th µg/l 10% CV µg/l Abbott AxSYM ADV Abbott ARCHITECT < Abbott i-stat Beckman Coulter Access Accu biomerieux Vidas Ultra Inverness Biosite Triage 0.05 <0.05 NA Inverness Biosite Triage (r) NA Mitsubishi Chemical PATHFAST Ortho Vitros ECi ES Radiometer AQT Response Biomedical RAMP 0.03 < Roche hstnt Roche Elecsys < Roche Cardiac Reader <0.05 <0.05 NA Siemens Centaur Ultra Siemens Dimension RxL Siemens Immulite 2500 STAT Siemens Immulite 1000 Turbo 0.15 NA 0.64 Siemens Stratus CS Siemens VISTA Tosoh AIA II 0.06 < IFCC

8 Hs Troponin Assays Analytical characteristics of contemporary sensitive troponin assays Assay LoD µg/l 99th µg/l 10% CV µg/l Siemens Centaur Ultra Analytical characteristics of high sensitive troponin assays Assay LoD µg/l 99th µg/l 10% CV µg/l Beckman Coulter Access hs-ctni Roche Elecsys hs-ctnt Abbott Architect STAT hstni Analytical characteristics of super sensitive troponin assays Assay LoD µg/l 99th µg/l 10% CV µg/l Nanosphere hs-ctni Singulex hs-ctni

9 Detectable Troponin in Acute and Chronic HF

10 Prognosis and Troponin in Acute and Chronic HF

11 Mechanisms of Cardiac Troponin Release in Heart Failure

12 Gutenberg Health Study Distribution of high sensitive Troponin I among 5000 apparently healthy german individuals

13 Gutenberg Health Study (GHS) Gutenberg Heart Study < 3.4 pg/ml (n=1779) pg/ml (n=1750) > pg/ml (n=447) > 12.7 pg/ml (n=163) p-value Age, mean ± SD, y ± ± ± ± < Sex, n (%), male 650 (36.5) 1009 (57.7) 320 (71.6) 120 (73.6) < Body mass index, mean ± SD, kg/m² ± ± ± ± 5.11 < Cardiovascular risk factors Active smoker, n (%) 371 (20.9) 329 (18.8) 74 (16.6) 23 (14.1) Ever smoking, n (%) 941 (53.0) 923 (52.8) 253 (56.9) 85 (52.1) 0.47 Diabetes, n (%) 92 (5.2) 124 (7.1) 63 (14.1) 37 (22.7) < Dyslipidemia, n (%) 342 (19.2) 638 (36.5) 194 (43.4) 62 (38.0) < Family history of MI, n (%) 306 (17.2) 302 (17.3) 89 (19.9) 28 (17.2) 0.57 Hypertension, n (%) 717 (40.3) 974 (55.7) 323 (72.3) 104 (63.8) < Obesity, n (%), BMI>30 kg/m² 322 (18.1) 485 (27.7) 144 (32.2) 61 (37.4) < Cardiovascular Diseases History of MI, n (%) 21 (1.2) 55 (3.1) 40 (9.0) 20 (12.3) < Prevalent CAD, n (%) 46 (2.6) 81 (4.7) 50 (11.5) 21 (13.2) < Medicated Heart Failure, n (%) 17 (1.0) 17 (1.0) 16 (3.6) 6 (3.7) < 0.001

14 Gutenberg Health Study (GHS) Gutenberg Heart Study < 3.4 pg/ml (n=1779) pg/ml (n=1750) > pg/ml (n=447) > 12.7 pg/ml (n=163) p-value Age, mean ± SD, y ± ± ± ± < Sex, n (%), male 650 (36.5) 1009 (57.7) 320 (71.6) 120 (73.6) < Body mass index, mean ± SD, kg/m² ± ± ± ± 5.11 < Cardiovascular risk factors Active smoker, n (%) 371 (20.9) 329 (18.8) 74 (16.6) 23 (14.1) Ever smoking, n (%) 941 (53.0) 923 (52.8) 253 (56.9) 85 (52.1) 0.47 Diabetes, n (%) 92 (5.2) 124 (7.1) 63 (14.1) 37 (22.7) < Dyslipidemia, n (%) 342 (19.2) 638 (36.5) 194 (43.4) 62 (38.0) < Family history of MI, n (%) 306 (17.2) 302 (17.3) 89 (19.9) 28 (17.2) 0.57 Hypertension, n (%) 717 (40.3) 974 (55.7) 323 (72.3) 104 (63.8) < Obesity, n (%), BMI>30 kg/m² 322 (18.1) 485 (27.7) 144 (32.2) 61 (37.4) < Cardiovascular Diseases History of MI, n (%) 21 (1.2) 55 (3.1) 40 (9.0) 20 (12.3) < Prevalent CAD, n (%) 46 (2.6) 81 (4.7) 50 (11.5) 21 (13.2) < Medicated Heart Failure, n (%) 17 (1.0) 17 (1.0) 16 (3.6) 6 (3.7) < 0.001

15 Gutenberg Health Study (GHS) Gutenberg Heart Study < 3.4 pg/ml (n=1779) pg/ml (n=1750) > pg/ml (n=447) > 12.7 pg/ml (n=163) p-value Age, mean ± SD, y ± ± ± ± < Sex, n (%), male 650 (36.5) 1009 (57.7) 320 (71.6) 120 (73.6) < Body mass index, mean ± SD, kg/m² ± ± ± ± 5.11 < Biomarker CRP, median (IQR), mg/l 1.50 (0.50/3.00) 1.80 (1.10/3.50) 2.00 (1.20/4.10) 2.30 (1.20/4.88) < NT-proBNP, median (IQR), pg/ml (27.94/103.10) (25.39/114.61) (41.12/240.07) (51.68/654.90) < HDL, mean ± SD, mg/dl ± ± ± ± < LDL, mean ± SD, mg/dl ± ± ± ± < Triglycerides, median (IQR), mg/dl (73.00/136.00) (84.00/155.00) (92.00/168.37) (93.17/158.57) < Creatinine, median (IQR), mg/dl 0.84 (0.76/0.93) 0.89 (0.80/0.99) 0.94 (0.84/1.02) 0.97 (0.87/1.08) < egfr, mean ± SD, ml/min for 1.73m² Cardiac structure and function ± ± ± ± < Diastolic dysfunction, n (%) 261 (15.4) 401 (24.6) 153 (39.5) 44 (34.4) < E/E', median (IQR) 6.62 (5.54/8.03) 7.11 (5.82/8.87) 7.80 (6.18/9.76) 8.10 (6.43/10.00) < Systolic dysfunction, n (%) 85 (4.9) 99 (5.7) 50 (11.8) 27 (18.6) < Ejection Fraction (Simpson), mean ± SD, % ± ± ± ± < Left ventricular hypertrophy, n (%) 139 (7.8) 209 (11.9) 93 (20.9) 57 (35.2) < Left ventricular wall mass, median (IQR), g (113.63/166.55) (130.59/188.79) (146.59/214.45) (152.90/243.69) < 0.001

16 Gutenberg Health Study (GHS) Gutenberg Heart Study < 3.4 pg/ml (n=1779) pg/ml (n=1750) > pg/ml (n=447) > 12.7 pg/ml (n=163) p-value Age, mean ± SD, y ± ± ± ± < Sex, n (%), male 650 (36.5) 1009 (57.7) 320 (71.6) 120 (73.6) < Body mass index, mean ± SD, kg/m² ± ± ± ± 5.11 < Biomarker CRP, median (IQR), mg/l 1.50 (0.50/3.00) 1.80 (1.10/3.50) 2.00 (1.20/4.10) 2.30 (1.20/4.88) < NT-proBNP, median (IQR), pg/ml (27.94/103.10) (25.39/114.61) (41.12/240.07) (51.68/654.90) < HDL, mean ± SD, mg/dl ± ± ± ± < LDL, mean ± SD, mg/dl ± ± ± ± < Triglycerides, median (IQR), mg/dl (73.00/136.00) (84.00/155.00) (92.00/168.37) (93.17/158.57) < Creatinine, median (IQR), mg/dl 0.84 (0.76/0.93) 0.89 (0.80/0.99) 0.94 (0.84/1.02) 0.97 (0.87/1.08) < egfr, mean ± SD, ml/min for 1.73m² Cardiac structure and function ± ± ± ± < Diastolic dysfunction, n (%) 261 (15.4) 401 (24.6) 153 (39.5) 44 (34.4) < E/E', median (IQR) 6.62 (5.54/8.03) 7.11 (5.82/8.87) 7.80 (6.18/9.76) 8.10 (6.43/10.00) < Systolic dysfunction, n (%) 85 (4.9) 99 (5.7) 50 (11.8) 27 (18.6) < Ejection Fraction (Simpson), mean ± SD, % ± ± ± ± < Left ventricular hypertrophy, n (%) 139 (7.8) 209 (11.9) 93 (20.9) 57 (35.2) < Left ventricular wall mass, median (IQR), g (113.63/166.55) (130.59/188.79) (146.59/214.45) (152.90/243.69) < 0.001

17 Gutenberg Health Study (GHS) Gutenberg Heart Study < 3.4 pg/ml (n=1779) pg/ml (n=1750) > pg/ml (n=447) > 12.7 pg/ml (n=163) p-value Age, mean ± SD, y ± ± ± ± < Sex, n (%), male 650 (36.5) 1009 (57.7) 320 (71.6) 120 (73.6) < Body mass index, mean ± SD, kg/m² ± ± ± ± 5.11 < Vascular structure and function Endothelial Function Flow mediated dilation, mean ± SD, % 9.03 ± ± ± ± 4.52 < Reflection index (Post - Pre), mean ± SD Intima-Media Thickness ± ± ± ± < IMT (right), median (IQR), mm 0.59 (0.52/0.68) 0.64 (0.55/0.73) 0.69 (0.60/0.80) 0.69 (0.61/0.79) < IMT (left), median (IQR), mm 0.60 (0.53/0.68) 0.65 (0.56/0.75) 0.71 (0.61/0.84) 0.70 (0.61/0.81) < IMT (mean), median (IQR), mm 0.60 (0.54/0.68) 0.64 (0.56/0.74) 0.71 (0.62/0.80) 0.70 (0.63/0.78) < Carotid atherosclerosis Plaques 1, n (%) 466 (26.3) 795 (45.5) 266 (59.6) 98 (60.9) < Number of Plaques, median (IQR), % 0 (0/1) 0 (0/2) 1 (0/4) 1 (0/4) < Ankle brachial index ABI (right), mean ± SD 1.07 ± ± ± ± ABI (left), mean ± SD 1.06 ± ± ± ±

18 Detectable Troponin in Acute and Chronic HF

19 Decompensated Heart Failure Tn measured in 84,872 of 105,388 patients of the Acute Decompensated Heart Failure National Registry (ADHERE) Pooled Tn I and Tn T measurements, not controlled for the assay platform Peacock WF et al, NEJM, 2008

20 Pulmonary Embolism n = 156 normotensive patients with pulmonary embolism Lankeit M et al, EHJ, 2010

21 Secondary Prevention hstnt was measured in n= 3679 patients with stable CAD of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial median follow-up time 5.2 years, 125 cardiovascular deaths Omland T et al, NEJM, 2009

22 Cardiac troponin Cardiac troponin and heart failure Cardiac troponin and intermediate phenotypes of heart failure Sensitive cardiac troponin and how to differentiate between early myocardial infarction and extracoronary sources like heart failure Highly sensitve cardiac troponin in the population

23 Keller T et al. NEJM, 2009 Real World Diagnosis of AMI

24 Real World Diagnosis of AMI Keller T et al. NEJM, 2009 Reichlin T et al. NEJM, 2009

25 Real World Diagnosis of AMI Reichlin T et al, NEJM J, 2009

Definition of AMI Type 1 - Acute Myocardial Infarction Detection of rise and/or fall of cardiac biomarkers (preferably troponin) above the 99 th percentile of the upper reference limit together with

26 Definition of AMI Type 1 - Acute Myocardial Infarction Detection of rise and/or fall of cardiac biomarkers (preferably troponin) above the 99 th percentile of the upper reference limit together with ischemia with a least one of the following: - Ischemic symptoms - ECG changes of new ischemia (new ST-T changes or new LBBB) - Development of pathologic Q waves in the ECG - Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality Recommended Biomarkers for diagnosing Myocardial infarction: - Preferably: Peak value of troponin above the 99 th percentile of the upper reference limit within 24hrs after index event measured with a CV 10% Thygesen K et al, JACC, Eur Heart J, Circ, 2007

27 Troponin Dynamics n=381 patients, n=52 AMI VITROS Troponin I ES assay; LoD ug/l, 99th percentile ug/l, 10% CV at ug/l. Chest pain onset to presentiation median 3.9 h, Time between Tn sampling 6 h Apple FS et al., Clinical Chemistry, 2009

034 ug/l. Chest pain onset to presentiation median 3.

28 Troponin Dynamics n=381 patients, n=52 AMI VITROS Troponin I ES assay; LoD ug/l, 99th percentile ug/l, 10% CV at ug/l. Chest pain onset to presentiation median 3.9 h, Time between Tn sampling 6 h Apple FS et al., Clinical Chemistry, 2009

29 Troponin Dynamics Patientswith initially negative TnT (Roche 4 th Gen.), n=31 UAP, n=26 AMI Roche hstnt assay; LoD 3 ng/l, 99 th percentile ng/l, 10% CV at 13 ng/l Chest pain onset to presentiation median 2.2h AMI, 10h UAP Time between Tn sampling 3 and 6 h Giannitis E et al., Clinical Chemistry, 2010

25 ng/l, 10% CV at 13 ng/l Chest pain onset to presentiation median 2.

30 Troponin Dynamics Patientswith initially negative TnT (Roche 4 th Gen.), n=31 UAP, n=26 AMI Roche hstnt assay; LoD 3 ng/l, 99 th percentile ng/l, 10% CV at 13 ng/l Chest pain onset to presentiation median 2.2h AMI, 10h UAP Time between Tn sampling 3 and 6 h Giannitis E et al., Clinical Chemistry, 2010

31 Troponin Dynamics 1h change 2h change n=836 patients, n=108 AMI Roche hstnt assay; LoD 3 ng/l, 99 th percentile 14 ng/l, 10% CV at 13 ng/l Siemens TnI-Ultra assay; LoD 6 ng/l, 99 th percentile 40 ng/l, 10% CV at 30 ng/l Reichlin T et al., Circulation, 2011

Bundeswehrzentralkrankenhaus Koblenz Patients admitted with

Herzzentrum Hamburg-Eppendorf Serial blood sampling and ECG

troponin, ergometry, cath and clinical information ctnt

32 Study design Chest Pain Unit, II. Med. Klinik Universitätsmedizin Mainz Innere Medizin Bundeswehrzentralkrankenhaus Koblenz Patients admitted with supected acute myocardial infarction n = 1818 Universitäres Herzzentrum Hamburg-Eppendorf Serial blood sampling and ECG at admission, 3h and 6h Final diagnosis based on in-house troponin, ergometry, cath and clinical information ctnt (Roche) 99th <0.01; 10% CV 0.03 ctni (Dimension RxL) 99th 0.07; 10% CV 0.14 NCCP n = 1165 UAP n = 240 AMI n = 413

33 High Sensitive Troponin Delta Change High Sensitive Troponin I 99th percentile at 29 pg/ml Sensitivity (CI) Specificity (CI) PPV (CI) NPV (CI) On admission > 99th percentile 82.6 (77.7,86.9) 91.8 (89.9,93.5) 74.4 (69.2,79.2) 94.8 (93.2,96.1) After 3 hours > 99th percentile 98.6 (96.4,99.6) 90.0 (87.9,91.8) 73.9 (69.2,78.3) 99.5 (98.8,99.9) On admission or after 3 hours > 99th percentile AND Change 20% 60.6 ( ) 96.7 ( ) 84.2 ( ) 89.5 ( ) Change 30% 56.0 ( ) 97.9 ( ) 88.3 ( ) 88.5 ( ) Change 50% 50.4 ( ) 99.0 ( ) 93.4 ( ) 87.4 ( ) Change 75% 44.7 ( ) 99.1 ( ) 93.3 ( ) 86.1 ( ) Change 100% 41.8 ( ) 99.3 ( ) 94.4 ( ) 85.6 ( ) Change 150% 37.2 ( ) 99.3 ( ) 93.8 ( ) 84.6 ( ) Change 200% 34.8 ( ) 99.5 ( ) 95.1 ( ) 84.1 ( ) Change 250% 33.0 ( ) 99.6 ( ) 95.9 ( ) 83.7 ( ) Change 266%* 33.0 ( ) 99.6 ( ) 95.9 ( ) 83.7 ( )

Cardiac troponin Cardiac troponin and heart failure Cardiac troponin and intermediate phenotypes of heart failure Sensitive cardiac troponin and how

34 Cardiac troponin Cardiac troponin and heart failure Cardiac troponin and intermediate phenotypes of heart failure Sensitive cardiac troponin and how to differentiate between early myocardial infarction and extracoronary sources like heart failure Highly sensitve cardiac troponin in the population

35 Primary Prevention n=3546 de Lemos JA et al., JAMA, 2010

36 Primary Prevention Heart failure Cardiov. Mortality n=4221 defilippi CR et al., JAMA, 2010

37 Scottish Heart Health Study (SHHS)

38 Highly Sensitive Troponin I MORGAM Scottish Heart Health Cohort hs Troponin I and Risk Prediction

39 Critical Issues for Success Highly sensitive test systems for troponin assessment improve diagnosis of acute myocardial infarction but results in detectable levels related to extracoronary causes. Troponin levels in acute and chronic heart failure are associaated with impaired outcome. In comparision with established heart failure markers like (Nt-pro)BNP or MRproANP, hs troponin does not provide specific information for the diagnosis of acute or chronic heart failure Highly sensitive troponin in the population might identify those individuals suffering from incident heart failure this offers biomarker guided primary preventive stratgegies. Highly sensitive troponin is strongly associated with echo-phenotypes of diastolic and systolic heart failure in ranges far below the decision criteria for AMI diagnosis.

10 Ways to Make the Use of High Sensitivity Cardiac Troponin Values Easier and Better

10 Ways to Make the Use of High Sensitivity Cardiac Troponin Values Easier and Better Allan S. Jaffe, MD.* Consultant - Cardiology & Laboratory Medicine Professor of Medicine Chair, CCLS Division, Department