I markers biochimici nelle CPU Learning Center Firenze 2 Ottobre 2001 Filippo Ottani, MD Bentivoglio

Possibile Ruolo dei Marcatori Biochimici nel Paziente con Dolore Toracico Sospetta Ischemia Miocardica Acuta (sintomi + probabilità malattia) ECG-12D ST sopraslivellato riperfusione estensione necrosi Ischemia ECG No Ischemia ECG Marker - Marker + Marker - Ricovero Med Ricovero UTIC (in base ad indicatori clinici di rischio) Dimissione (in base a indicatori clinico-strumentali)

Marcatori Biochimici nel Paziente con Sospetta Ischemia Miocardica Acuta Diagnosi precoce di infarto miocardico acuto Riconoscimento rapido del paziente con angina instabile ad alto rischio

Vantaggi di una Strategia di Valutazione Basata su Marcatori Biochimici Facilità di approccio al paziente Rapidità nella disponibilità del risultato Semplicità di interpretazione del dato ottenuto Adattabilità ad ogni contesto operativo(POC)

Marcatori Biochimici in Uso nella Diagnosi di I.M.A.

Cumulative Proportion of Patients with a Sample Above the URL According to the Size of Infarction Time after T0 (hours) Myo CK-MB mass cTnT De Winter et al, Circulation 1995

Negative Predictive Value of Several Biomarkers in a Group of Patients with Chets Pain and an AMI Probability <75% NPV Time after T0 (hours) De Winter et al, Circulation 1995

Diagnosi Precoce di I. M. A Diagnosi Precoce di I.M.A. Diagnostic Marker Cooperative Study 995 pz con dolore toracico, 119 (12,5%) con IMA performance diagnostica dei test a 6 ore dall’inizio dei sintomi Zimmerman et al, Circulation 1999

90’ Exclusion of AMI by Use of POC Testing of Myoglobin And Troponin I 0, 90 min 0, 90 min, 3 h Sensitivity Specificity Sensitivity Specificity Myo 84.6 (74–92) 73.0 (70–76) 84.6 (74–92) 71.1 (68–74) CK-MB 83.1 (72–91) 83.0 (80–86) 89.2 (79–96) 81.6 (79–84) cTnI 76.9 (65–86) 79.0 (76–82) 87.7 (77–94) 69.8 (66–73) Myo/ CKmb 92.3 (83–98) 67.5 (64–71) 92.3 (83–98) 65.7 (62–69) Myo/cTnI 96.9 (89–100) 59.7 (56–63) 96.9 (89–100) 53.1 (49–57) -VE Predictive +VE Predictive -VE Predictive +VE Predictive Value Value Value Value Myo 98.2 (97–99) 21.4 (16–27) 98.3 (97–99) 20.4 (16–26) CK-MB 98.3 (97–99) 29.8 (23–37) 98.9 (98–100) 29.9 (24–38) cTnI 97.5 (96–99) 24.2 (18–31) 98.5 (97–99) 20.2 (16–25) Myo/ CKmb 99.0 (98–100) 19.7 (15–25) 99.0 (98–100) 19.0 (15–24) Myo/cTnI 99.6 (98–100) 17.3 (14–22) 99.5 (98–100) 15.2 (12–19) McCord, Circulation 2001; 104: 1483

SMARTT Trial: Sensitivity and Specificity for Serum Markers for AMI Gibler WB et al, JACC 2000;36:1500 Marker Sensistivity % Specificity Myoglobin 64.1 90.2 CK-MB 52.6 96.7 Either myoglobin or 72 88.5

Event-free Survival (%) Survival During 30 Days Follow UP According to Troponin Status:Death or Nonfatal MI Troponin I negative 60 80 90 100 70 Troponin T negative ST-Segment Depression Event-free Survival (%) Troponin I positive Troponin T positive 10 20 30 Days Hamm CW, NEJM 1997;337:1648

Le Troponine nei Pazienti con Sospetta Ischemia Miocardica Acuta (considerazioni basate sui dati di Hamm et al, NEJM 1997)

Incidenza di Eventi Cardiaci Maggiori Entro 72 Ore in Pazienti con Dolore Toracico Polanczyk et al, JACC 1998

Performance Diagnostica di Troponina I e CK-MB in Pazienti con Dolore Toracico Polanczyk et al, JACC 1998

Uso dei Marcatori Biochimici nei Pazienti con Dolore Toracico Polanczyk et al, Am J Cardiol 1999 Chest Pain Study Population (n=1051) Yes (n=170) Elevated CK-MB mass ST elevation on ECG GROUP A 85% (145/170) No (n=881) ECG with changes consistent with ischemia No (n=696) Elevated troponin I Yes (n=35) No (n=150) GROUP B 26% (9/35) GROUP C 13% (19/150) GROUP D 4% (26/696)

SENSITIVITY SPECIFICITY VALORE COMBINATO DI TROPONINA E IMAGING PERFUSIONALE Kontos et al, Circulation 1999 Tc MIBI Adm TnI TnI >2.0 TnI >1.0 SENSITIVITY SPECIFICITY 97 100 92 90 90 81 82 80 75 70 60 53 50 45 40 30 30 26 26 17 17 20 10 10 10 10 MI Revasc Sig Dis MI or SD

Prediction of Cardiac Events by Troponin I in Patients with Chest Pain % MI MI/D MI/D/ Sig CAD Sig CAD Sig Comp Kontos, JACC 2000; 36: 1818

Performance Diagnostica di Troponina I in Pazienti con Dolore Toracico Kontos, JACC 2000; 36: 1818

CHECKMATE 30-Day Outcomes MMS-1 MMS-2 LL single marker Positive Negative Positive Negative Positive Negative n=149 n=641 P n=114 n=684 P n=44 n=807 P No. % No. % No. % No. % No. % No. % Baseline testing Death 3 2.0 0 0.007 2 1.8 1 0.2 0.055 0 4 0.5 1.000 MI 17.5 3.0 0.001 21.1 3.1 0.001 13.6 5.1 0.029 Revasc 14.8 5.7 0.001 18.4 5.5 0.001 25.0 7.3 <0.001 Death or MI 18.8 3.0 0.001 21.9 3.2 0.001 13.6 5.5 0.038 Death, MI, or 27.5 7.3 0.001 33.3 7.3 0.001 36.4 10.3 0.001 revasc Serial testing Death 3 1.3 1 0.1 0.045 2 1.1 2 0.3 0.163 1 1.2 3 0.3 0.308 MI 18.0 1.7 0.001 20.0 2.2 0.001 55.3 0.9 0.001 Revasc 14.5 4.9 0.001 17.8 4.7 0.001 32.1 5.1 0.001 Death or MI 18.9 1.8 0.001 20.6 2.5 0.001 55.3 1.3 0.001 Death, MI, or 27.6 5.8 0.001 31.1 6.3 0.001 67.1 5.9 0.001 n=228 n=725 n=180 n=775 n=85 n=883 Circ 103(14):1832, 2001 CP1000342-4

CHECKMATE Predictors of Death or Myocardial Infarction at 30 Days Odds ratio Wald c2 P (95% CI) Model c2* C-index Baseline testing models MMS-1 62.2 0.804 MMS-1 status 25.1 0.0001 5.4 (2.8-10.40) Prior infarction 7.6 0.0060 2.7 (1.3-5.5) Female sex 6.6 0.0104 0.38 (0.18-0.80) Abnormal ECG 4.2 0.0396 2.0 (1.0-4.0) MMS-2 69.9 0.823 MMS-2 status 27.6 0.0001 5.9 (3.0-11.4) Prior infarction 8.6 0.0033 2.9 (1.4-6.0) Female sex 8.7 0.0032 0.31 (0.14-0.68) Diabetes 5.0 0.0247 2.3 (1.1-4.9) Abnormal ECG 4.0 0.0446 2.0 (1.0-4.0) * Log-likelihood Circ 103(14):1832, 2001 CP1000342-5

CHECKMATE Predictors of Death or Myocardial Infarction at 30 Days Odds ratio Wald c2 P (95% CI) Model c2* C-index Serial testing models MMS-1 87.4 0.848 MMS-1 status 42.3 0.0001 9.6 (4.9-19.0) Female sex 5.6 0.0177 0.45 (0.23-0.87) Prior anginal pain 5.0 0.0257 2.0 (1.1-3.7) Abnormal ECG 4.5 0.0345 2.0 (1.1-3.7) MMS-2 80.5 0.839 MMS-2 status 42.6 0.0001 7.8 (4.2-14.4) Female sex 6.8 0.0090 0.41 (0.21-0.80) Prior anginal pain 6.5 0.0110 2.2 (1.2-4.0) Abnormal ECG 5.9 0.0152 2.2 (1.2-4.1) * Log-likelihood Circ 103(14):1832, 2001 CP1000342-6

CHECKMATE Chest Pain Duration by Baseline Marker Status Symptom onset to baseline sample (hr) Myoglobin Positive 4.4 (1.9, 12.5) Negative 5.5 (2.5, 11.0) CK-MB Positive 5.6 (2.9, 11.1) Negative 5.4 (2.4, 11.6) Troponin I Positive 6.4 (3.0, 14.3) Negative 5.3 (2.4, 11.0) Data are median (25th, 75th percentiles) Circ 103(14):1832, 2001 CP1000342-7

CHECKMATE-PROBLEMS A multi-marker strategy with sensitive cut points was compared to local CKMB with ? cut points; troponin was only used if CKMB was not available. In 31 patients total CK was relied upon. The gold standard was CKMB elevation - no rising and falling pattern, new Q waves or if doctor diagnosed. Sampling was at zero, 3 and 6 hours after onset of symptoms and beyond if in hospital - no results of those measurements. Myoglobin testing identified 35 ? MIs (23%) and one death. Troponin testing early added 2 deaths and 70 MIs and might have added more had the late data on the 4 patients with negative CKMBs who died been added.

CHECKMATE - CONCLUSIONS Troponin is substantially better than CKMB for diagnosis of MI and for defining prognosis. Cut points chosen for sensitivity work better for early detection. Myoglobin may identify patients with MI earlier.

Prevalenza e Significato Diagnostico delle Alterazioni ECG nel Multicenter Chest Pain Study Rouan et al, AJC 1989

Relations between cTnT and CK-MB results Occurrence of long-term adverse events de Filippi et al., JACC 35, 7; 2000:1827-34

1-year Prognosis in Patients with Chest Pain and Absence of Electrocardiographic Ischemia According to Troponin Status de Filippi et al., JACC 35, 7; 2000:1827-34

CONCLUSIONI I marker biochimici permettono una valutazione rapida, universalmente praticabile, del paziente con sospetta ischemia miocardica acuta La dimostrazione precoce di danno miocardico consente di individuare i pazienti con I.M.A. e la maggioranza di quelli con A.I. ad alto rischio di morte e I.M.A. non-fatale L’esclusione del danno miocardico non è da sola sufficiente a decidere la dimissione del paziente, dal momento che anche in assenza di danno miocardico si possono verificare complicanze gravi e diventare necessaria la rivascolarizzazione

Prognostic Value of Troponin T, Myoglobin, and CK-MB mass in Emergency Room Patients with Chest Pain 1.00 0.75 0.50 60 180 120 Normal CK-MB Abnormal CK-MB 1.00 0.75 0.50 60 180 120 Normal Myo Abnormal Myo Time (d) Time (d) Normal cTnT Abnormal cTnT 1.00 0.75 0.50 60 180 120 % of Event-free Survival Time (d) De Winter Heart 1996; 75:235