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 Paris, August 27 th, 2011

DECLARATION OF CONFLICT OF INTEREST none

Use of Biomarkers

Cardiac troponin Cardiac Troponin I/T

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

Keller et al., Circulation 2011

Troponin Assays Assay LoD µg/l 99th µg/l 10% CV µg/l Abbott AxSYM ADV 0.02 0.04 0.16 Abbott ARCHITECT <0.01 0.028 0.032 Abbott i-stat 0.02 0.08 0.10 Beckman Coulter Access Accu 0.01 0.04 0.06 biomerieux Vidas Ultra 0.01 0.01 0.11 Inverness Biosite Triage 0.05 <0.05 NA Inverness Biosite Triage (r) 0.01 0.056 NA Mitsubishi Chemical PATHFAST 0.008 0.029 0.014 Ortho Vitros ECi ES 0.012 0.034 0.034 Radiometer AQT90 0.0095 0.023 0.039 Response Biomedical RAMP 0.03 <0.1 0.21 Roche hstnt 0.002 0.014 0.014 Roche Elecsys 2010 0.01 <0.01 0.030 Roche Cardiac Reader <0.05 <0.05 NA Siemens Centaur Ultra 0.006 0.04 0.03 Siemens Dimension RxL 0.04 0.07 0.14 Siemens Immulite 2500 STAT 0.1 0.2 0.42 Siemens Immulite 1000 Turbo 0.15 NA 0.64 Siemens Stratus CS 0.03 0.07 0.06 Siemens VISTA 0.015 0.045 0.04 Tosoh AIA II 0.06 <0.06 0.09 IFCC

Hs Troponin Assays Analytical characteristics of contemporary sensitive troponin assays Assay LoD µg/l 99th µg/l 10% CV µg/l Siemens Centaur Ultra 0.006 0.04 0.03 Analytical characteristics of high sensitive troponin assays Assay LoD µg/l 99th µg/l 10% CV µg/l Beckman Coulter Access hs-ctni 0.0020 0.0086 0.0086 Roche Elecsys hs-ctnt 0.001 0.013 0.012 Abbott Architect STAT hstni 0.0034 0.029 0.0052 Analytical characteristics of super sensitive troponin assays Assay LoD µg/l 99th µg/l 10% CV µg/l Nanosphere hs-ctni 0.0002 0.0028 0.0005 Singulex hs-ctni 0.00009 0.0101 0.00088

Detectable Troponin in Acute and Chronic HF

Prognosis and Troponin in Acute and Chronic HF

Mechanisms of Cardiac Troponin Release in Heart Failure

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

Gutenberg Health Study (GHS) Gutenberg Heart Study < 3.4 pg/ml (n=1779) 3.4-6.7 pg/ml (n=1750) >6.7-12.7 pg/ml (n=447) > 12.7 pg/ml (n=163) p-value Age, mean ± SD, y 52.12 ± 10.53 56.44 ± 10.62 61.16 ± 10.14 62.47 ± 10.05 < 0.001 Sex, n (%), male 650 (36.5) 1009 (57.7) 320 (71.6) 120 (73.6) < 0.001 Body mass index, mean ± SD, kg/m² 26.28 ± 4.56 27.78 ± 4.88 28.59 ± 4.65 29.01 ± 5.11 < 0.001 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) < 0.001 NT-proBNP, median (IQR), pg/ml 56.04 (27.94/103.10) 58.76 (25.39/114.61) 102.80 (41.12/240.07) 189.40 (51.68/654.90) < 0.001 HDL, mean ± SD, mg/dl 60.02 ± 16.02 54.84 ± 15.05 52.50 ± 15.05 50.99 ± 13.87 < 0.001 LDL, mean ± SD, mg/dl 133.96 ± 32.17 149.65 ± 35.21 150.33 ± 42.31 140.77 ± 39.34 < 0.001 Triglycerides, median (IQR), mg/dl 98.44 (73.00/136.00) 112.00 (84.00/155.00) 123.00 (92.00/168.37) 118.00 (93.17/158.57) < 0.001 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) < 0.001 egfr, mean ± SD, ml/min for 1.73m² Cardiac structure and function 85.22 ± 13.21 84.36 ± 17.62 81.09 ± 14.60 76.88 ± 18.12 < 0.001 Diastolic dysfunction, n (%) 261 (15.4) 401 (24.6) 153 (39.5) 44 (34.4) < 0.001 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) < 0.001 Systolic dysfunction, n (%) 85 (4.9) 99 (5.7) 50 (11.8) 27 (18.6) < 0.001 Ejection Fraction (Simpson), mean ± SD, % 64.31 ± 5.81 63.88 ± 5.82 62.26 ± 7.09 59.49 ± 11.54 < 0.001 Left ventricular hypertrophy, n (%) 139 (7.8) 209 (11.9) 93 (20.9) 57 (35.2) < 0.001 Left ventricular wall mass, median (IQR), g 138.45 (113.63/166.55) 158.73 (130.59/188.79) 173.86 (146.59/214.45) 194.76 (152.90/243.69) < 0.001

Gutenberg Health Study (GHS) Gutenberg Heart Study < 3.4 pg/ml (n=1779) 3.4-6.7 pg/ml (n=1750) >6.7-12.7 pg/ml (n=447) > 12.7 pg/ml (n=163) p-value Age, mean ± SD, y 52.12 ± 10.53 56.44 ± 10.62 61.16 ± 10.14 62.47 ± 10.05 < 0.001 Sex, n (%), male 650 (36.5) 1009 (57.7) 320 (71.6) 120 (73.6) < 0.001 Body mass index, mean ± SD, kg/m² 26.28 ± 4.56 27.78 ± 4.88 28.59 ± 4.65 29.01 ± 5.11 < 0.001 Vascular structure and function Endothelial Function Flow mediated dilation, mean ± SD, % 9.03 ± 5.55 7.44 ± 4.66 6.56 ± 4.53 6.70 ± 4.52 < 0.001 Reflection index (Post - Pre), mean ± SD Intima-Media Thickness -2.83 ± 13.19-1.96 ± 13.32-0.67 ± 13.36-0.45 ± 12.18 < 0.001 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) < 0.001 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) < 0.001 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) < 0.001 Carotid atherosclerosis Plaques 1, n (%) 466 (26.3) 795 (45.5) 266 (59.6) 98 (60.9) < 0.001 Number of Plaques, median (IQR), % 0 (0/1) 0 (0/2) 1 (0/4) 1 (0/4) < 0.001 Ankle brachial index ABI (right), mean ± SD 1.07 ± 0.11 1.08 ± 0.12 1.07 ± 0.16 1.09 ± 0.16 0.030 ABI (left), mean ± SD 1.06 ± 0.11 1.07 ± 0.11 1.07 ± 0.18 1.08 ± 0.16 0.023

Detectable Troponin in Acute and Chronic HF

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

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

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

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

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

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 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

Troponin Dynamics n=381 patients, n=52 AMI VITROS Troponin I ES assay; LoD 0.012 ug/l, 99th percentile 0.034 ug/l, 10% CV at 0.034 ug/l. Chest pain onset to presentiation median 3.9 h, Time between Tn sampling 6 h Apple FS et al., Clinical Chemistry, 2009

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 13.25 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

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

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

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 (54.7-66.4) 96.7 (95.4-97.8) 84.2 (78.5-89.0) 89.5 (87.5-91.3) Change 30% 56.0 (50.0-61.9) 97.9 (96.7-98.7) 88.3 (82.6-92.6) 88.5 (86.5-90.4) Change 50% 50.4 (44.4-56.3) 99.0 (98.1-99.5) 93.4 (88.2-96.8) 87.4 (85.3-89.3) Change 75% 44.7 (38.8-50.7) 99.1 (98.3-99.6) 93.3 (87.7-96.9) 86.1 (84.0-88.1) Change 100% 41.8 (36.0-47.8) 99.3 (98.5-99.7) 94.4 (88.8-97.7) 85.6 (83.4-87.5) Change 150% 37.2 (31.6-43.2) 99.3 (98.5-99.7) 93.8 (87.5-97.5) 84.6 (82.4-86.6) Change 200% 34.8 (29.2-40.6) 99.5 (98.8-99.8) 95.1 (89.0-98.4) 84.1 (81.9-86.2) Change 250% 33.0 (27.5-38.8) 99.6 (99.0-99.9) 95.9 (89.8-98.9) 83.7 (81.5-85.8) Change 266%* 33.0 (27.5-38.8) 99.6 (99.0-99.9) 95.9 (89.8-98.9) 83.7 (81.5-85.8)

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

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

Scottish Heart Health Study (SHHS)

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

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.