Dr John T. Parissis Attikon University Hospital Athens, Greece Clinical value of Troponin and NT-proBNP Assessment in acute cardiac setting Dr John T. Parissis Attikon University Hospital Athens, Greece

Disclosures Grants: ALARM investigator received research grants by Abbott US and Orion Pharma Horonaria: received horonaria for advisory boards and lectures from Novartis, Pfizer, Menarini , Servier and Roche Diagnostics Journals: Associate Editor of EJHF GLs: Member of task force

Urgent cardiac conditions with chest pain Acute coronary syndromes Acute pulmonary embolism Acute pericarditis and /or myocarditis Aortic dissection

Less than 20% of pre-hospital chest pain patients have AMI1 1: Stengaard C. et al. Quantitative point-of.care Troponin T measurement for diagnosis and prognosis in patients with a suspected acute myocardial infarction. Am. J. Cardiol. 2013; 112:1361-6

Universal Definition of Acute Myocardial Infarction The ESC-ACC-AHA-WHF Criteria Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit together with evidence of ischemia with at least one of the following Symptoms of ischemia ECG changes of new ischemia (new ST-T changes or new LBBB) Development of pathologic Q waves Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality Thygesen, Alpert, White. Universal Definition of Myocardial Infarction 2007 EHJ, JACC, CIRC

Chest pain with signs and symptoms of ACS AMI can be STEMI or NSTEMI (ST Elevated MI) NSTEMI (Non ST Elevated MI) ECG with ST depression, T-wave inversion or no ECG abnormalities ECG with ST elevation Troponin test Elevated Troponin None elevated Troponin STEMI - Normal therapy NSTEMI - Normal therapy Retest with Troponin to Rule-Out or Rule-In AMI Acute angioplasty (PPCI=primary percutaneous coronary intervention) Normally ST Elevated ECG (STEMI=ST Elevated Myocardial Infarction) changes in combination with signs and symptoms of Acute Myocardial Infarction sends the patient directly to the cath lab. Patients with signs and symptoms and without ST Elevated ECGs (NSTEMI=No ST Elevated Myocardial Infarction) or even normal ECGs have to use Troponin biomarkers to detect AMI patients. ECG showing ST elevation4 Normal ECG pattern3 Stillman et al (2011). Int J Cardiovasc Imaging 27:7–24 Antman et al (2004). Circulation 110:588–636 Available at http://www.ecglibrary.com/norm.html, July 2012 Available at http://www.ambulancetechnicianstudy.co.uk/ecgbasics.html, July 2012 Medical therapy / coronary angiography within 24 hours Not AMI Other reason for chest pain ≈60% of all AMI patients are NSTEMI1 NSTEMI patients have higher mortality 1: Rogers W et al. Am Heart J 2008;156:1026-34

Clinical Classification of different Types of Myocardial Infarction Type 1 Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as plaque erosion or rupture Type 2 Myocardial infarction secondary to ischemia due to imbalance between oxygen demand and supply e.g. coronary spasm            Type 3 Sudden cardiac death with symptoms of myocardial ischemia, accompanied by new ST elevation or LBBB, or verified coronary thrombus by angiography, but death occurring before blood samples could be obtained Type 4a Myocardial infarction associated with PCI Type 4b Myocardial infarction associated with stent thrombosis Type 5 Myocardial infarction associated with CABG Thygesen, Alpert, White. Universal Definition of Myocardial Infarction 2007 EHJ, JACC, CIRC

Elevations of cTn in the absence of ACS - Cardiac Causes Congestive heart failure Arrhythmias, heart block Cardiac contusion, ablation, pacing, cardioversion, biopsy Cardiomyopathy: HCM, Takotsubo Inflammation - e.g. myocarditis, endocarditis Rhabdomyolysis with cardiac injury Infiltrative diseases, e.g., amyloidosis, haemochromatosis, sarcoidosis, scleroderma Drug toxicity, e.g., adriamycin, herceptin, clozapine Aortic dissection, aortic valve disease

Variation of Troponin in frequent cardiac conditions

Elevations of cTn in the absence of ACS Non-cardiac Causes Acute and chronic renal failure Acute neurological disease, including stroke, or subarachnoid haemorrhage Pulmonary embolism, severe pulmonary hypertension Exacerbation of COPD Hypothyroidism Phaeochromocytoma Burns affecting >30% of body surface area Severe trauma Critically ill patients with respiratory failure, or sepsis Snake bites

Non-acute myocardial infarction-related causes of elevated high-sensitive troponin T in the emergency room: a cross-sectional analysis

Elevated high-sensitive troponin T on admission is an indicator of poor long-term outcome in patients with subarachnoid haemorrhage

Non-ACS troponin elevation: Iatrogenic causes Invasive procedures: Heart transplantation Congenital defect repair Radiofrequency catheter ablation Lung resection ERCP Non-invasive procedures Cardioversion Lithotripsy Pharmacologic sources Chemotherapy Other medication Kelley et al. Clinical Chemistry 2009

Markers of Cardiac Necrosis

Biomarkers for risk stratification in ACS

Clinical decision making and biomarkers in ACS

Twerenbold R et al. Eur Heart J 2012;33:579-586 Diagnostic accuracy at presentation as quantified by the area under the receiver operating characteristic (ROC) curves for a contemporary cardiac troponin in the diagnosis of acute myocardial infarction according to chest pain onset. Diagnostic accuracy at presentation as quantified by the area under the receiver operating characteristic (ROC) curves for a contemporary cardiac troponin assay (black, fourth-generation cardiac troponin T) and four sensitive or high-sensitive cardiac troponin assays (red, Siemens cTnI Ultra; blue, Abbott cTnI Architect; green, Roche high-sensitivity cTnT; orange, Roche cTnI) in the diagnosis of acute myocardial infarction according to chest pain onset. Twerenbold R et al. Eur Heart J 2012;33:579-586

Advantages of troponin T vs troponin I in clinical practice A. More accurate sensitivity / specificity ratio B. More validated diagnostic prospective protocols C. More standardized time-dependent algorithms D. Less limitations in clinical practice (e.g muscular disorders, renal dysfunction) E. More validated strategies that connect POC measurements with laboratory assays

Earlier diagnosis of AMI Detecting more AMIs earlier Acute myocardial infarction 80 70 60 50 40 30 20 10 57 32 31 22 55 +33% +11% Number of patients 46 45 Double click anywhere on the graph area in order to change values of the graph 20 cTnT cTnT-hs cTnT cTnT-hs Diagnosis of AMI on admission Final diagnosis

Twerenbold R et al. Eur Heart J 2012;33:579-586 The differential diagnosis of high-sensitive cardiac troponin T (hs-cTnT) levels is highly dependent on the absolute level. The differential diagnosis of high-sensitive cardiac troponin T (hs-cTnT) levels is highly dependent on the absolute level. Twerenbold R et al. Eur Heart J 2012;33:579-586

Diagnostic performance of Hs-TnT at presentation in renal dysfunction. Renal dysfunction (defined as Modification of Diet in Renal Disease–estimated glomerular filtration rate <60 mL・min−1・1.73 m−2). Conclusions—Sensitive cTnT assay maintains high diagnostic accuracy in patients with renal dysfunction. To ensure the best possible clinical use, assay-specific optimal cutoff levels, which are higher in patients with renal dysfunction, should be considered Circulation. 2015;131:2041-2050

High-sensitive Tn Levels in the Community (White HD, Am Heart J, 159(6): 933–6, 2010) Use of cTnT-hs to diagnose myocardial infarction Patient with symptoms of MI* Baseline cTnT-hs <14 ng/L Change <50% Change ≥50% Retest cTnT-hs 3 hours later ≥14 to < 53 ng/L ≥53 ng/L Retest cTnT -hs 3 hours later Retest cTnT-hs 6 hours later to rule out MI Change <20% Change ≥20% Adverse prognosis Retest cTnT-hs at 6, 12 hours Myocardial infarction *To make the diagnosis of MI, there must also be evidence of ischemia manifesting as symptoms or evident on electrocardiogram, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

One hour Rule-Out and Rule-In algorithm with cTnT-hs1 Acute chest pain patients presenting to Emergency Department Under prospective validation with the TRAPID-AMI trial 0h<12ng/L and Delta 1h< 3ng/L Others 0h≥52ng/L or Delta 1h≥ 5ng/L Rule-out Observational zone Rule-in Sensitivity: 100% NPV: 100% 60% of the patients Prevalence of AMI: 8% 23% of the patients Specificity: 97% PPV: 84% 17% of the patients 1: APACE Trial 2012: http://www.ncbi.nlm.nih.gov/pubmed/22892889

with suspected NSTEMI to the ER ESC guidelines 2015: 0 h/1 h rule-in and rule-out algorithms using high sensitivity cardiac troponins (hs-cTn) assays in patients presenting with suspected NSTEMI to the ER

Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a high-sensitivity cardiac troponin T assay (CAMJ 2015)

38% of the AMI patients had a pre-hospital cTnT>50ng/L Early pre-hospital Troponin T test to identify AMI patients and patients with high mortality risk1. AMI distribution Primary discharge diagnosis Mortality rate per year Patients (%) Final diagnose POC cTnT test result Chest pain in pre-hospital care (ambulance) 924 patients ≤ 50 ng/L Not AMI 698 (76%) 0.04 Cardiac Other AMI 119 (13%) 0.06 62% > 50 ng/L 34 (4%) 0.38 73 (8%) 0.17 38% 38% of the AMI patients had a pre-hospital cTnT>50ng/L 1: Stengaard C. et al. Quantitative point-of.care Troponin T measurement for diagnosis and prognosis in patients with a suspected acute myocardial infarction. Am. J. Cardiol. 2013; 112:1361-6

POC cTnT working together with Elecsys LAB cTnT-hs STEMI (ST Elevated MI) NSTEMI (Non ST Elevated MI) ECG with ST elevation ECG with ST depression Normal ECG pattern cobas h 232 Troponin T Early identify patients with elevated POC cTnT>50ng/L in 12 min Elevated POC cTnT None elevated POC cTnT STEMI - Normal therapy NSTEMI - Normal therapy Elecsys cTnT-hs Rule Out/In within 1hr using cTnT-hs Acute angioplasty (PPCI=primary percutaneous coronary intervention) Normally ST Elevated ECG (STEMI=ST Elevated Myocardial Infarction) changes in combination with signs and symptoms of Acute Myocardial Infarction sends the patient directly to the cath lab. Patients with signs and symptoms and without ST Elevated ECGs (NSTEMI=No ST Elevated Myocardial Infarction) or even normal ECGs have to use Troponin biomarkers to detect AMI patients. ECG showing ST elevation4 Normal ECG pattern3 Stillman et al (2011). Int J Cardiovasc Imaging 27:7–24 Antman et al (2004). Circulation 110:588–636 Available at http://www.ecglibrary.com/norm.html, July 2012 Available at http://www.ambulancetechnicianstudy.co.uk/ecgbasics.html, July 2012 Medical therapy / coronary angiography within 24h Not NSTEMI Other reason for chest pain Slide 28

Combining POC results with lab assays according to the duration of chest pain

Combining POC results with lab assays according to the duration of chest pain

with suspected NSTEMI to the ER ESC guidelines 2015: 0 h/1 h rule-in and rule-out algorithms using high sensitivity cardiac troponins (hs-cTn) assays in patients presenting with suspected NSTEMI to the ER

Biomarkers for APE mortality prediction 100pts, 15 deaths (8 APE deaths) 1 - Swoistość 1,0 ,8 ,5 ,3 0,0 Czułość NTproBNP 600pg/ml AUC = 0.795 1-specificity sensitivity AUC = 0.751 sensitivity 1-specificity AUC=0.751 cTnT 0.07ng/ml >0.07ng/ml sens. 89%, spec. 87% HR 18.1 (95% CI: 3.6–90.2) 7600pg/ml 40 days APE realted mortality was 8%. ROC analysis defined two NTproBNP levels. Levels over 7600pg.ml chracterized high risk group ithd HR of 7.3. Pateints with low proBNP formed group without deaths. For troponin T cut off of 0.07ng/ml was found . It defined high risk gruop with high sensitivity and speceificity and with HR of 18.   1-specificity >7600pg/ml sens. 63%, spec. 83% HR 7.3 (CI 95%: 1.7–30.6) <600 pg/ml no deaths, Kostrubiec M. et al. EHJ 2005 35

Proposed risk assessment in APE Biomarkers are included in the risk assessment in APE (ESC Guidelines on APE, 2008)

Clinical Outcomes in Patients Hospitalized with Acute Heart Failure All-cause mortality: In hospital 3 - 11% At 60 - 90 days 10 - 16% Readmissions: At 60 - 90 days 20 - 25% Mean length of stay 6 -10 days Recently completed clinical trials, such as Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF), Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF), Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF), and the ADHERE Registry and Euro Heart Failure survey showed that the admissions for heart failure bear a grim prognosis. While the in-hospital mortality is relatively low (3-4%), the 60-90 day post discharge event rate is very high: the mortality is in the range of 10% and the readmission rates are as high as 25%. Combining these figures with a mean length of stay of 6-10 days, the picture becomes pretty sobering. Cuffe SM et al. JAMA. 2002; 287: 1541 Gheorghiade M et al. JAMA. 2004; 291: 1963 Gattis WA et al. J Am Coll Cardiol. 2004; 43: 1534 Cleland JGF et al. Eur Heart J. 2003; 24: 442

Signs and symptoms in ALARM-HF Signs and Symptoms: All AHF vs ADCHF vs Novo AHF patients Sample = All AHF patients (5,060) vs ADCHF (3,341) vs De Novo AHF patients (1719) Parissis et al. Eur J Heart Fail 2011; Follath et al Int Care Med 2011

Diagnostic flowchart for patients with suspected HF ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

Incidence of Detectable Troponin in acute and chronic HF Kociol et al. JACC2010;56:1071–8

Prognostic value of hs- troponin T in patients with ADHF and non-detectable conventional troponin T levels Parissis et al. IJC 2012

Kociol et al. J Am Coll Cardiol. 2010;56(14):1071-1078. Signs and Symptoms Differentiating AMI From AHF in the Setting of Positive Troponin Kociol et al. J Am Coll Cardiol. 2010;56(14):1071-1078.

Maisel. Cardiovasc Diagn Ther 2012;2(2):147-164 Strength of evidence for individual biomarkers for diagnosis and prognosis of HF Maisel. Cardiovasc Diagn Ther 2012;2(2):147-164

Recommendations for Biomarkers in HF Biomarker, Application Setting COR LOE Natriuretic peptides Diagnosis or exclusion of HF Ambulatory, Acute I A Prognosis of HF Achieve GDMT Ambulatory IIa B Guidance of acutely decompensated HF therapy Acute IIb C Biomarkers of myocardial injury Additive risk stratification Acute, Ambulatory Biomarkers of myocardial fibrosis   ΑΗΑ/ ACC guidelines on HF 2013

ESC HF GLs 2016: Recommendations regarding applied diagnostic measurements

«Ανάλυση κόστους/αποτελεσματικότητας της εξέτασης του Ν-τελικού τμήματος του νατριουρητικού πεπτιδίου τύπου pro-B Elecsys® για τη διάγνωση και την πρόγνωση της καρδιακής ανεπάρκειας στην Ελλάδα*» Οικονομική Ανάλυση ΜΕΙΩΣΗ ΤΟΥ ΚΟΣΤΟΥΣ ΔΙΑΓΝΩΣΗΣ   Μείωση Ευρώ Μείωση του αριθμού ακτινογραφιών 850 (εξετάσεις) 11.947,11 Μείωση του αριθμού ηχωκαρδιογραφιών 639 (εξετάσεις) 11.675,27 Μείωση του κόστους αρχικής νοσηλείας (ασθενείς που δεν είχαν διαγνωστεί με NT-proBNP) 11.149 (ημέρες) 6.780.332,98 Συνολική μείωση του κόστους διάγνωσης 6.803.955,36 ΜΕΙΩΣΗ ΤΟΥ ΚΟΣΤΟΥΣ ΠΡΟΓΝΩΣΗΣ/ΠΑΡΑΚΟΛΟΥΘΗΣΗΣ   Μείωση Ευρώ Μείωση του κόστους νοσηλείας (με παρακολούθηση μέσω NT-proBNP) 2.319 (ημέρες) 1.410.309,26 Μείωση του κόστους επανεισαγωγής 491 (ασθενείς) 1.762.886,57 Συνολική μείωση του κόστους πρόγνωσης/παρακολούθησης 3.173.195,83 Η προβλεπόμενη καθαρή εξοικονόμηση από τη χρήση της εξέτασης NT-proBNP για την καθιέρωση της διάγνωσης και της πρόγνωσης της οξείας ΚΑ σε ασθενείς που προσέρχονται με δύσπνοια εκτιμήθηκε στα €9.259.096,35. Value in health 18 (2015) A335–A766

«Ανάλυση κόστους/αποτελεσματικότητας της εξέτασης του Ν-τελικού τμήματος του νατριουρητικού πεπτιδίου τύπου pro-B Elecsys® για τη διάγνωση και την πρόγνωση της καρδιακής ανεπάρκειας στην Ελλάδα*» Λειτουργική ανάλυση Δυνητική λειτουργική μείωση Μείωση του χρόνου παραμονής στο ΤΕΠ (εν αναμονή της διάγνωσης) 2,0 ώρες/ασθενή ή 37.192,36 ώρες για όλους τους ασθενείς Μείωση του αριθμού αρχικών νοσηλειών ασθενών με δύσπνοια 1.890 ασθενείς Μείωση του αριθμού αρχικών νοσηλειών ασθενών με συμφορητική καρδιακή ανεπάρκεια στη γενική κλινική 8.473,05 ημέρες Μείωση των ασθενών με ΣΚΑ στη γενική κλινική χάρη στην παρακολούθηση με NT-proBNP 1.762 ημέρες Συνολική μείωση ημερών νοσηλείας (γενική κλινική) 10.235 ημέρες Μείωση του αριθμού αρχικών νοσηλειών ασθενών με συμφορητική καρδιακή ανεπάρκεια στη μονάδα εντατικής θεραπείας 2.675,70 ημέρες Μείωση των ασθενών με ΣΚΑ στη μονάδα εντατικής θεραπείας χάρη στην παρακολούθηση με NT-proBNP 557 ημέρες Συνολική μείωση ημερών νοσηλείας (εντατική θεραπεία) 3.232 ημέρες Μείωση αριθμού επανεισαγωγών 491 ασθενείς Value in health 18 (2015) A335–A766

TAKE HOME MESSAGES (I) - POC assay of troponin offers a rapid rule-in with results in less than 12 minutes at the cut-off point of ≥ 50 ng/L. - It is a very useful tool for identifying these ACS patients with high mortality risk who require accelerated treatment It is an effective approach to rule out early patients with low pre-test probability (low risk) and without significant ECG findings. It can help clinicians to effectively make a differential diagnosis between ACS and other cardiac or non-cardiac causes of chest pain (PE, pericarditis, aortic dissection etc. ).

TAKE HOME MESSAGES (II) This assay is also useful to stratify risk in patients with PE and pericarditis In general, it is more effective and useful in patients with longer duration of chest pain . In cases with initial values lower than 50 ng/ml, it can be used in combination with LAB using high sensitive Troponin T and the 1 hour TRAPID-AMI algorithm to Rule-out & Rule-In AMI. More prospective trials are needed in order to indentify if this technology is cost effective in real clinical practice.