Basta un minimo movimento di troponina per fare diagnosi di. per fare diagnosi di

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1 Basta un minimo movimento di troponina per fare diagnosi di SCA sindrome coronarica acuta? Stefano Savonitto Stefano Savonitto Divisione di Cardiologia Arcispedale S. Maria Nuova Reggio Emilia Divisione di Cardiologia Arcispedale S. Maria Nuova Reggio Emilia Basta un minimo movimento di troponina per fare diagnosi di sindrome coronarica acuta?

2 Cardiac troponins are structural to the myocite De Lemos JA. JAMA 2013;309:2262-9

3 Cardiac troponins are released following myocardial cell injury De Lemos JA. JAMA 2013;309:2262-9

4 3 Universal definition of myocardial infarction Thygesen K. Eur Heart J 2012;33:

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6 the advantages of high-sensitivity assays should be weighed against the disadvantage of reduced clinical specificity.

7 High-sensitivity c-troponin assays No real consensus exists on how to define a highsensitivity assay in analytical or clinical terms With improvements to diagnostic sensitivity, the diagnostic clinical specificity will decrease to as low as 65-75% The real challenge is how to define and select healthy individuals Apple FS. Clin Chem 2010

8 Detection of hstnt elevations in the general population The Dallas Heart Study 3546 individuals, aged 30 to 65 years 1% 25%* * 3.4% above URL Standard assay Highly Sensitive Assay De Lemos JA. JAMA 2013;309:2262-9

9 Variables associated with chronic elevations of hs/troponins Age: Recommendations about age-dependent ctn cutoff limits cannot be made at present Hypertension Diabetes CKD LVH De Lemos JA. JAMA 2013;309:2262-9

10 Diagnosi finale di pazienti consecutivi con elevazione di ctni (>0.04 ng/ml) ammessi a Pronto Soccorso pazienti ammessi a PS in 3 mesi, misurazioni seriate ctni 701 (23.8%) con elevazioni di ctni Type 2 MI spesso associato a droghe Javed U. Am J Cardiol 2009;104:9-13

11 Chronic non-acs-related ctn elevations Condition Proposed Mechanism Prevalence Prognostic impact Stable CAD Chronic HF Diabetes Multifactorial: plaque burden, microvasc dysf, strain, CKD, diabetes. Strain (LVEDP). RAA and symp activation. Microvascular dysfunction Subclinical KD, microvasc dysf, microembolization 10% Predictor of CV death and HF. Up to 50% Predictor of all cause death and rehosp for HF 15-20% Predictor of CV death Pulmonary art. hypertension RV strain, reduced systemic or coronary perfusion, hypoxaemia 4-14% Predictor of death and functional impairment (6MWT) Chronic Kidney disease Underlying CAD and HF, reduced clearance 20-80% depending on cutoff (only ctnt FDA approved) Predictor of death at univariate. Strong collinearity with egfr Modified from Giannitsis E & Katus HA. Nat Rev Cardiol 2013;10:623 34

12 Acute non-acs-related ctn elevations Condition Proposed Mechanism Prevalence Prognostic impact Myocarditis Inflammatory Poorly correlated with outcome SV tachycardia Atrial Fibrillation Multifactorial: O 2 mismatch w. or w/o CAD, pressure/volume overload, microvascular Up to 30% Detectable in 55% of NVAF (RE-LY) Controversial Correlated to SSE in AF (RE-LY & ARISTOTLE) Acute heart 10-15% Worse baseline Myocardial strain failure characteristics & worse outcome Acute pulmonary embolism Sepsis Right ventricular strain; reduced systemic and/or coronary perfusion O 2 mismatch, endotox, myocarditis, vasopressors, DIC 16-50% Highly correlated with outcome 60% Predictor of all-cause mortality Modified from Giannitsis E & Katus HA. Nat Rev Cardiol 2013;10:623 34

13 ACS related vs non ACS-related hs/troponin elevations and survival ACS Non-ACS Alcalai R. Arch Intern Med 2007;167:276-81

14 3 Universal definition of myocardial infarction Thygesen K. Eur Heart J 2012;33:

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16 Curve di rilascio di ctnt dopo STEMI riperfuso, embolia polmonare o maratona 1. The steeper the slope, the higher the likelihood of NSTEMI as compared with non-acs conditions. 2. Absolute changes are better than relative changes, especially in pts with low baseline values Giannitsis, E. & Katus, H. A. Nat. Rev. Cardiol. 2013;10:623 34

17 Biochemical markers of myocardial damage The key role of following kinetics Melanson S. Circulation 2007

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19 Ogni cosa al suo posto In addition to clinical indicators of myocardial ischaemia, a ctn value >99th percentile of a healthy reference population, together with a relevant temporal change in ctn concentration, are required for diagnosis of acute MI (specifically non-st-segment elevation MI [NSTEMI], as STEMI is diagnosed by ST-segment elevation on the electrocardiogram and is not the target of biomarker testing). Giannitsis, E. & Katus, H. A. Nat. Rev. Cardiol. 2013;10:623 34

20 ACS: Initial Decision-making Algorithm 2007 ESC guidelines ECG ST ST Neg. T normal AMI High Risk Troponin Low Risk Arrival & > 6-12 hrs.

21 ACS Any risk stratification is valid only once you have entered the door of the ACS scenario

22 ACS Patients with acute ischemic symptoms + ischemic ECG and/or elevated biochemical markers

23 Cardiac Troponin Metaanalysis in ACS: Death OR (re) MI 30 days F/U Study Troponin +ve Troponin -ve Peto OR (95% CI Fixed) Hamm,1992 Wu, 1995 Ohman, 1996 Cin, 1996 Stubbs, 1996 Antman, 1996 Galvani, 1997 Luscher, 1997 Solymoss, 1997 Ottani, 1997 Olatidoye, 1998 Benamer, 1998 Rebuzzi, 1998 Brisic, 1998 Antman, 1998 Capture, / 23 8 / / / / / / / / / 47 5 / / 60 7 / 14 3 / 22 4 / / / 51 3 / / / 48 6 / 52 8 / / / / 74 1 / 47 3 / 94 2 / / 88 2 / / / [3.22,42.57] [6.89,144.19] 4.70 [1.74,12.67] [5.24,61.25] 1.46 [0.51,4.19] 3.80 [1.80,8.03] 6.55 [1.32,32.38] 2.48 [1.28,4.76] 2.43 [0.73,8.05] 6.62 [1.98,22.10] [17.39, ] [3.87,48.33] [5.18,123.23] 7.96 [0.97,65.12] 1.11 [0.35,3.53] 5.48 [2.76,10.87] Subtotal 180 / / [3.77,6.45] Ohman, 1996 Stubbs, 1996 Gusto Ill, / / / / / / [1.56,7.33] 3.38 [0.77,14.96] 2.82 [2.30,3.45] Subtotal 235 / / [2.35,3.47] Total 415 / / [2.94,4.03] Ottani F. Am Heart J 2000;140: Low Risk High Risk

24 EHS ACS-II Mortality by Discharge Diagnosis AMI UAP In hospital day day

25 Troponin and Risk Stratification The DUKE CCU experience 1-year mortality TnT TnI T-Wave or Minor 4% 0 5% 0 ST Depression 12% 4% 13% 6% ST Elevation 13% 5% 12% 6% Confounders 15% 7% 19% 5% Ohman, NEJM 1996 Christenson, Clin Chem 1998

26 Prognostic impact of elevated CK on admission in relation to baseline risk in ACS Mortality 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% Inverted T Waves Elevated CK Normal CK Days to death ST Depression Elevated CK Normal CK Days to death Savonitto S. ANE 2001;6:64-77

27 Risk stratification in ACS: the take home message Annals Electrocardiology 2001;6:64-77

28 GUSTO IIb database (NSTEACS) OR for one-year mortality Età (75 vs 55 anni) FC (85 vs 64 bpm) NSTEMI all ingresso Diabete Classe Killip II Classe Killip III/IV Precedente IMA Precedente scompenso PA diast (90 vs 70 mmhg) Precedente angina Severa BPCO PA sist (150 vs 120 mmhg) Precedente BPAC Sesso (F/M) Adjusted χ Armstrong P: Circulation 1998;98:1860

29 Early risk stratification in ACS: The importance of heart failure

30 Acute chest pain in the Emergency Room Identification and examination of low-risk patients 596 pts with chest pain admitted to ER at Brigham No single variable could identify low-risk pts as well as a normal ECG A combination of 3 variables sharp or stabbing pain, no history of angina or MI and pain with pleuritic or positional characteristics or pain reproduced by palpation of the chest wall - defined a very low-risk group in which the ECG did not add accuracy and was potentially misleading Standard cardiac enzymes were of almost no use as an emergency room indicator of myocardial infarction Lee TH. Arch Intern Med 1985;145:65

31 ECG: the ideal tool for diagnosis, risk stratification, Decision making and therapeutic monitoring in ACS Ideally, a clinical tool is useful for diagnosis, risk stratification, clinical decision making, and monitoring therapy. Few existing tools address the statistical requirements of each stage of clinical use. The 12-lead electrocardiogram (ECG) is one exception and is central to each stage via diagnosis, prognosis, clinical decision making, and monitoring therapy. Scirica BJ. JACC 2010;55:

32 Probability of 30-D death by sum of ST depression on the admission ECG: the GUSTO IIb ECG corelab Probability of 30-day death 0,35 0,3 0,25 0,2 0,15 0, Q (n=2493) % 3-vessel disease % LM disease 3 Q (n=1366) 4 Q (n=1333) Incidence of 3VD and LMCA disease by quartiles of Σ ST depression Probability of death 0,05 95% confidence limits sum of ST depression (mm) Savonitto S. Eur Heart J 2005;26: 2106

33 Adjusted Probability of Death By Max CK Ratio across the spectrum of ACS: the GUSTO IIb study Adjusted Probability of Death to Six Months Mortality at 6 months 0,25 0,2 Non ST elevation (n=7,749) 0,15 0,1 ST elevation (n=3,976) 0, Maximum CK Ratio Savonitto S. JACC 2002;39:22-9

34 Death or MI at 6 months: GUSTO IIb database CK-MB ratio Savonitto S. JACC 1999

35 Predictive capacity of the model EMAI DEATH (re-mi) model X 2 C-index Clinical model without biomarkers Clinical model with biomarkers DEATH Clinical model without biomarkers Clinical model with biomarkers Oltrona L. Am Heart J 2004; 148:

36 Max CPK ratio across the ACS spectrum The GUSTO IIb study Savonitto S. JACC 2002;39:22-9

37 Patients with worse baseline characteristics Show less enzyme elevations no ST elev Previous MI % 35 Max CPK ratio Max CPK ratio 0-1 >1-2 >2-5 >5 Previous 0-1 >1-2 >2-5 >5 angina 85 % Prior PTCA % >1-2 >2-5 >5 Prior CABG 0-1 >1-2 >2-5 >5 % Savonitto S. JACC 2002;39:22-9

38 Impact of abciximab on top of ASA and clopidogrel depends on patients baseline risk Death or MI at 30 days P= P=0.91 P= Placebo Abciximab Placebo Abciximab Placebo Abciximab ISAR REACT 1 Stable patients ISAR REACT 2 NSTEACS TnT - ISAR REACT 2 NSTEACS TnT + Kastrati A,.NEJM 2004, JAMA 2006

39 Possibili meccanismi, fisiopatologici e non, di elevazioni ctn Giannitsis, E. & Katus, H. A Nat. Rev. Cardiol. 2013;10:623 34