1. 1950196019701980 1990 2000 AST in AMI CK in AMI electrophoresis for CK and LD isoenzymes INH for CK-MB RIA for myoglobin WHO criteria for AMI CK-MB mass assay cTnT in AMI cTnT in UA cTnI in AMI cTns to guide therapy cTns for risk stratific. AMI redefined

2. Biochemical Markers for Detecting Myocardial Necrosis 1) Maximal concentration of troponin T or I exceeding the 99th percentile of the reference values on at least one occasion during the first 24 h after the clinical event. 2) Maximal value of CK-MB (preferably CK-MB mass) exceeding the 99th percentile of the reference values on two successive samples, or maximal value exceeding twice the upper reference limit on one occasion during the first hours after the clinical event. Values for CK-MB should rise and fall. The Joint European Society of Cardiology/ American College of Cardiology Committee, September 2000

3. A causa della loro scarsa sensibilita e specificita, le determinazioni di aspartato amminotransferasi (AST), lattato deidrogenasi (LDH) totale e suoi isoenzimi, CK totale e attivita catalitica del suo isoenzima MB dovrebbero essere considerate come obsolete. GdS Intersocietario ANMCO-SIBioC-SIMeL Marcatori di lesione miocardica Panteghini M et al. G Ital Cardiol 1999;29:810

4. MYOCARDIAL INFARCTION REDEFINED The term Myocardial Infarction should be used when evidence of cardiac damage exists, as detected by cardiac proteins in a clinical setting consistent with myocardial ischemia. The Joint European Society of Cardiology/ American College of Cardiology Committee, Sept 2000

5. Trauma (including contusion,ablation,pacing,firing, cardioversion,cardiac surgery) Congestive heart failure Hypertension Hypotension, often with arrhythmias Postoperative non-cardiac surgery Chronic renal failure Critically ill patients, esp. with diabetes Hypothyroidism Myocarditis Post percutaneous coronary interventions Pulmonary embolism Sepsis Amyloidosis Cardiotoxicity from cancer therapy Elevation of Cardiac Troponins in Patients without Overt Ischemic Heart Disease

6. Use of Biochemical Markers in Acute Coronary Syndromes Sampling frequency marker admission+4h+8 h +12h or next morning early e.g. myoglobinXX(X) troponin XXXX (X) indicates optional determination Committee on Standardization of Markers of Cardiac Damage

7. Myoglobin is at present the most sensitive marker for excluding early AMI with an optimum timing of sampling at patient presentation and approx. 4 h later. Panteghini M et al. The sensitivity of cardiac markers: an evidence-based approach. Clin Chem Lab Med 1999;37:1097

8. CK-MBMyoglobin + Troponin Pos Predictive Value Neg Predictive Value Accuracy Zaninotto M et al., 1999

9. TWO MARKERS PROTOCOL - OUTCOME DATA - ( Caragher et al., Arch Pathol Lab Med 2000) Number of patients discharged in <24 h Control groupTest group 20 of 71 41 of 81 28% 50.6% P = 0.0048 Number of patients discharged in <12 h Control groupTest group 16 of 71 30 of 81 22% 37% P = 0.0522

10. TWO MARKERS PROTOCOL - OUTCOME DATA - ACS-Negative Patients ACS-Positive Patients Caragher et al., Arch Pathol Lab Med 2000

11. Limpiego del marcatore precoce, sebbene di principio consigliabile, può essere comunque valutato in funzione del reale impatto che linformazione da esso fornita (elevato valore predittivo negativo 4 h dopo lammissione del paziente) può ottenere sulle decisioni cliniche relative al paziente stesso (dimissione vs osservazione). Gruppo di Studio Intersocietario ANMCO-SIBioC-SIMeL Marcatori di lesione miocardica Panteghini M et al., G Ital Cardiol 1999

12. Use of Biochemical Markers in Acute Coronary Syndromes Sampling frequency Committee on Standardization of Markers of Cardiac Damage For hospitals without an area for rapid ruling out of chest pain patients (decisions are not made within the first few hours after admission), the following protocol is recommended: marker admission +6 h +12h or next morning cardiac troponin X XX

13. Owen A et al., Ann Clin Biochem 2001 Troponin T: role in altering patient management and enabling earlier discharge from a district general hospital Unstable angina ptsMedian length of stay Median cost Test group4 days £ 910 Control group5 days £ 1125 Non-ischemic chest pain pts Test group2 days £ 235 Control group9 days £ 1125 Control indicates use of the traditional enzymatic approach. Test indicates use of cardiac troponin T protocol.

14. Rate of inaccurate estimation of interval between onset of symptoms and admission in patients with AMI = 15% Bholasingh R, De Winter RJ, Nieuwenhuijs AB, Sanders GT. Proceedings of The Challenge of Acute Coronary Syndromes - The Lancet Conference. Copenhagen, 1999

15. Question How much necrosis is needed to make diagnosis of MI? In the purest physiologic sense, any detectable necrosis is a MI. Answer

16. Cardiac death or MI, % Time from inclusion (days) Troponin T, g/L > 0.62 < 0.62 < 0.18 < 0.06 160 140120 100 80 604020 0 4 8 12 16 20 24 Lindahl B et al., 1996

17. FRISC-2 Study Lindahl B et al., 2000 cTnT, g/L<0.01 0.01<0.03 0.03<0.10 0.10 n=541n=1615n=656n=1500n=892n=1264 12-m death, %1.75.9*2.75.7 **3.45.9** 12-m death/AMI, %8.518.0 *10.217.9 *13.816.9 ns * P <0.001; ** P <0.01; ns = not significant

18. Morrow DA et al., Clin Chem 2000 Risk of Death or MI at 43 Days Lower RiskHigher Risk Immuno-12.2 (1.3 - 3.6) ACS:1802.8 (1.5 - 5.1) RxL3.0 (1.5 - 5.7) RR (95% CI) Baseline cTnI 0.10 g/L

19. Dimension RxL ACS:180 Immuno 1 Events (%) at 43 days P = NS P = 0.0001 P = 0.0002 P = 0.08 P = 0.0004 P < 0.0001 P = NS P = 0.009 P = 0.006

20. An increased value for cardiac troponin should be defined as a measurement exceeding the 99th percentile of a reference control group. MYOCARDIAL INFARCTION REDEFINED The Joint European Society of Cardiology/ American College of Cardiology Committee, Sept 2000

21. Committee on Standardization of Markers of Cardiac Damage Recommendation: A total CV of less than 10% at the myocardial infarction decision limit is recommended. This should provide an objective target for manufacturers of instruments and kits in the construction of new assays. Panteghini M et al., Quality specifications for cardiac troponin. Clin Chem Lab Med 2001

22. Imprecision around the Diagnostic Cutoff of Troponin Assays Assay Troponin, g/L CV,% Abbott AxSYM2.9010.0 Bayer ACS:1801.334.1 Bayer ACS:Centaur0.5213.0 Bayer Immuno 11.004.9 Beckman Access 2nd gen.0.0910.0 Biosite Triage0.3419.5 Dade Dimension RxL 2 gen.0.1411.4 Dade Opus 2nd gen.1.7025.6 Dade Stratus CS0.0814.0 BioMerieux Vidas0.278.4 DPC Immulite1.009.8 First Medical Alpha Dx0.307.4 Ortho-Clinical Diagn. Vitros0.3510.0 Roche Cardiac Reader0.3318.0 Roche Elecsys 3rd gen.0.11 3.6

23. In the context of clinical practice: For troponin assays that cannot meet the 10% CV recommendation at the 99th percentile, a predetermined higher concentration that meets the goal of 10% imprecision should be used as AMI cutoff until the goal of a 10% CV can be achieved at the 99th percentile.

24. Assay A Assay B 99 th URL

25. Implication of troponin assay imprecision for AMI diagnosis Assay Calculated 99 th URL (AMI cutoff) Concentration associated with a 10% CV Abbott AxSYM 0.50 g/L2.90 g/L (5.8 x URL) Bayer ACS:Centaur 0.15 g/L1.40 g/L (9.3 x URL) Dade Behring Dimension 0.05 g/L0.40 g/L (8 x URL) DPC Immulite 0.40 g/L1.20 g/L (3 x URL) Ortho Vitros 0.10 g/L0.35 g/L (3.5 x URL) Roche Elecsys 0.01 g/L0.03 g/L (3 x URL) Panteghini M, 2001

26. BIOCHEMICAL MARKERS IN ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION In these patients, biochemical markers may be useful: 1. to qualitatively estimate the MI size, 2. for early stratification of the subsequent risk, 3. to predict rate of failed primary PCI, 4. to detect the presence of complications such as re-infarction, 5. to monitor thrombolytic therapy. These applications are however optional and not definitively supported by scientific evidence.

27. Firenze, 10 ottobre 2001 Incontro Nazionale su La nuova definizione di infarto miocardico Obiettivo: ottimizzare luso dei marcatori di danno miocardico attraverso il raggiungimento di un consenso nei comportamenti nella pratica clinica, anche per favorire lintroduzione della nuova definizione di IM