I markers biochimici nelle CPU

Learning CenterFirenze

2 Ottobre 2001

Filippo Ottani, MD Bentivoglio

Sospetta Ischemia Miocardica Acuta(sintomi + probabilità malattia)

ECG-12DST sopraslivellato

Ischemia ECG No Ischemia ECG

Ricovero UTIC(in base ad indicatori

clinici di rischio)

Possibile Ruolo dei Marcatori Biochimici nel Paziente con Dolore Toracico

riperfusione estensione necrosi

Ricovero Med

Marker - Marker + Marker -

Dimissione(in base a indicatoriclinico-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.

Marker PM(D)

Tempo diElevazione

(ore)

Tempo diNormalizzazione

(ore)

SpecificitàMiocardica

CK-MB 86 000 3-12 48-72 Relativa

Mioglobina 17 800 1-4 24 Assente

Isoforme CK-MB

86 000 2-6 ? (= CK-MB) Relativa

Troponina T 33 000 3-12 5-14 Assoluta

Troponina I 23 500 5-12 5-10 Assoluta

Cumulative Proportion of Patients with a Sample Above the

URL According to the Size of Infarction

De Winter et al, Circulation 1995

0

25

50

75

100

3 4 5 6 7 8 12 16 20 24

Large AMI

Mid-size AMI

Small AMI

CumulativeProportion

Time after T0 (hours)

Myo

0

25

50

75

100

3 4 5 6 7 8 12 16 20 24

Small AMI

Mid-size AMI

Large AMI

CK-MB mass

0

25

50

75

100

3 4 5 6 7 8 12 16 20 24

Small AMI

Mid-size AMI

Large AMI

cTnT

Negative Predictive Value of Several Biomarkers in a Group of Patients with Chets Pain and an AMI Probability

<75%

0

25

50

75

100

3 4 5 6 7 8 12 16 20 24

Myo

CK-MB mass

CK_MB act

cTnT

NPV

Time after T0 (hours)De Winter et al, Circulation 1995

Diagnosi Precoce di I.M.A.Diagnostic Marker Cooperative Study

995 pz con dolore toracico, 119 (12,5%) con IMAperformance diagnostica dei test a 6 ore dall’inizio dei sintomi

Zimmerman et al, Circulation 1999

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)

90’ Exclusion of AMI by Use of POC Testing of Myoglobin And Troponin I

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 96.7Either myoglobin

orCK-MB

72 88.5

Survival During 30 Days Follow UP According to Troponin Status:Death or Nonfatal MI

0

60

80

90

100

70

0 10 20 30

Days

Eve

nt-

free

S

urv

ival

(%

)

Troponin I negative

Troponin T negative

Troponin I positive

Troponin T positive

ST-Segment Depression

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)

Quesito: Risposta Motivazione

I pazienti positividevono esserericoverati in UTIC?

SI L’incidenza di morte+ IMA non-fatale è19% a 30 gg, 12%durante la degenza

I pazienti negativipossono esseremandati a casa?

NO Più del 50% deinegativi sono statiricoverati, il 30% diquesti in UTIC

Incidenza di Eventi Cardiaci Maggiori Entro 72 Ore in Pazienti con Dolore Toracico

Polanczyk et al, JACC 1998

All Pts(n=1047)

Pts with MI(n=142)

Pts withUA (n=385)

Pts withNo MI or

UA (n=520)

1 major cardiacevent

94 (9%) 37 (26%) 56 (15%) 1 (0.2%)

Cardiac arrest 7 (0.7%) 1 (0.7%) 5 (1.3%) 1 (0.2%)

High degree AVblock

1 (0.1%) 0 1 (0.3%) 0

Intubation 5 (0.5%) 2 (1.4%) 3 (0.8%) 0

IABP 26 (2%) 17 (12%) 9 (6%) 0

Coronary revasc 80 (8%) 32 (23%) 48 (13%) 0

Performance Diagnostica di Troponina I e CK-MB in Pazienti con Dolore Toracico

Polanczyk et al, JACC 1998

All Pts Pts With No MI

CTnI CK-MB CTnI CK-MB

Sensitivity 47%

(44/99)

38%

(36/94)

26%

(15/57)

5%

(3/57)

Specificity 80%(763/953)

87%(827/953)

88%(749/848)

98%(827/848)

PPV 19%(44/234)

22%(36/162)

8%

(3/38)

13%

(3/24)

NPV 94%(763/813)

93%(827/885)

95%(749/791)

94%(827/881)

RR 3.1 3.4 2.6 2.1

Uso dei Marcatori Biochimici nei Pazienti con Dolore Toracico

Polanczyk et al, Am J Cardiol 1999

Chest PainStudy Population

(n=1051)

Elevated CK-MB massST elevation on ECG

ECG with changes consistent with ischemia

Elevated troponin I

GROUP A85% (145/170)

Yes(n=170)

No (n=881)

GROUP B26% (9/35)

GROUP C13% (19/150)

GROUP D4% (26/696)

No(n=696)

Yes (n=35) No (n=150)

VALORE COMBINATO DI TROPONINA E IMAGING PERFUSIONALE

Kontos et al, Circulation 1999

92

8175

82

90

17 17

45

97

26 26

53

101010

30

0

10

20

30

40

50

60

70

80

90

100

MI Revasc Sig Dis MI or SD

67

74 74 76

96 98 98 9894 96 96 97

0

10

20

30

40

50

60

70

80

90

100

MI Revasc Sig Dis MI or SD

Tc MIBI Adm TnI TnI >2.0 TnI >1.0

SENSITIVITY SPECIFICITY

Prediction of Cardiac Events by Troponin I in Patients with Chest Pain

58 61

77

41 43

0 1

18 1712

0

10

20

30

40

50

60

70

80

90

cTnI +VE

cTnI -VE

%

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

All Pts Nonischemic ECGonly

Sensitivity Specificity Sensitivity Specificity

MI 96%

(92-98)

93%

(92-94)

97%

(92-99)

94%

(93-95)

MI or death 92%

(87-95)

92%

(87-95)

90%

(84-94)

94%

(93-95)

MI/D or CAD 43%

(39-48)

95%

(94-96)

40%

(35-45)

95%

(94-96)

Complications 20%

(15-25)

96%

(95-97)

19%

(14-25)

95%

(94-96)

CAD 14%

(11-18)

95%

(94-96)

12%

(8.8-17)

95%

(94-96)

Kon

tos,

JA

CC

200

0; 3

6: 1

818

CHECKMATE30-Day Outcomes

Circ 103(14):1832, 2001 CP1000342-4

Positive Negative Positive Negative Positive Negativen=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 0.001revasc

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

MMS-1 MMS-2 LL single marker

n=228 n=725 n=180 n=775 n=85 n=883

CHECKMATEPredictors of Death or Myocardial Infarction at 30 Days

* Log-likelihood

Circ 103(14):1832, 2001 CP1000342-5

Odds ratioWald 2 P (95% CI) Model 2* 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)

CHECKMATEPredictors of Death or Myocardial Infarction at 30 Days

* Log-likelihood

Circ 103(14):1832, 2001 CP1000342-6

Odds ratioWald 2 P (95% CI) Model 2* 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)

CHECKMATEChest Pain Duration by Baseline Marker Status

Data are median (25th, 75th percentiles)Circ 103(14):1832, 2001 CP1000342-7

Symptom onset tobaseline sample (hr)

MyoglobinPositive 4.4 (1.9, 12.5)Negative 5.5 (2.5, 11.0)

CK-MBPositive 5.6 (2.9, 11.1)Negative 5.4 (2.4, 11.6)

Troponin IPositive 6.4 (3.0, 14.3)Negative 5.3 (2.4, 11.0)

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 andbeyond 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

ECG Finding % of TotalPopulation(n=7115)

% of Patientswith MI

(n=1024)

1 mm ST or Q waves >2leads

9% (605) 45% (461)

New ischemia 1 mm, ST2 leads

7% (531) 20% (203)

Other new ST or T changes<1 mm

10% (693) 14% (147)

Old MI or ischemia 9% (644) 5% (50)

Other new or oldabnormality

16% (1147) 5% (56)

Nonspecific ST-T changes 20% (1433) 7% (72)

Normal 29 % (2062) 4% (35)

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

0.500 60 180120

1.00

0.75

0.500 60 180120

1.00

0.75

0.500 60 180120

Time (d)

Time (d) Time (d)

Normal CK-MB Abnormal CK-MB Normal Myo Abnormal Myo

Normal cTnT Abnormal cTnT

% o

f E

ve

nt-

fre

e S

urv

iva

l

De Winter Heart 1996; 75:235