1950

1960

1970

1980

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

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

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

MYOCARDIAL INFARCTION MYOCARDIAL INFARCTION REDEFINEDREDEFINED

MYOCARDIAL INFARCTION MYOCARDIAL INFARCTION REDEFINEDREDEFINED

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

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

Use of Biochemical Markers in Acute Coronary Syndromes

Sampling Sampling frequencyfrequency

marker marker admissionadmission +4h+4h +8 h +8 h +12h +12h or next morningor next morning

early early e.g. myoglobine.g. myoglobin XX XX (X)(X)

troponin troponin XX XX XX XX

(X) indicates optional determination(X) indicates optional determination

Committee on Standardization of Markers of Cardiac Damage

“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

Disease Prevalence

0.0 0.2 0.4 0.6 0.8 1.0

Perf

orm

ance

Mea

sure

Val

ue

0.0

0.2

0.4

0.6

0.8

1.0

Disease Prevalence

0.0 0.2 0.4 0.6 0.8 1.0Pe

rfor

man

ce M

easu

re V

alue

0.0

0.2

0.4

0.6

0.8

1.0CK-MB Myoglobin +

Troponin

Pos Predictive Value

Neg Predictive Value

Accuracy

Zaninotto M et al., 1999

TWO MARKERS PROTOCOL- OUTCOME DATA -

(Caragher et al., Arch Pathol Lab Med 2000)

Number of patients discharged in <24 h

Control group Test group 20 of 71 41 of 81 28% 50.6% P = 0.0048

Number of patients discharged in <12 h

Control group Test group 16 of 71 30 of 81 22% 37% P = 0.0522

TWO MARKERS PROTOCOL- OUTCOME DATA -

Group Age Sex LOS # LabProc

TotalCost

LabCost

Control 64.4 M, 35F, 38

2.02 14.7 $ 2019 $ 189

Test 63.8 M, 39F, 42

1.62 12.3 $ 1635 $ 158

Control 69.0 M, 10F, 9

5.69 36.0 $ 7425 $ 462

Test 74.4 M, 7F, 8

4.56 23.6 $ 5164 $ 303

ACS-Negative Patients

ACS-Positive Patients

Caragher et al., Arch Pathol Lab Med 2000

L’impiego del marcatore precoce, sebbene di principio

consigliabile, può essere comunque valutato in funzione

del reale impatto che l’informazione da esso fornita

(elevato valore predittivo negativo 4 h dopo l’ammissione

del paziente) può ottenere sulle decisioni cliniche relative

al paziente stesso (dimissione vs osservazione).

Gruppo di Studio IntersocietarioANMCO-SIBioC-SIMeL “Marcatori di lesione miocardica”

Panteghini M et al., G Ital Cardiol 1999

Use of Biochemical Markers in Acute Coronary Syndromes

Sampling Sampling frequencyfrequency

Committee on Standardization of Markers of Cardiac Damage

For hospitals without an area for rapid ruling out of For hospitals without an area for rapid ruling out of chest pain patients (decisions are not made within chest pain patients (decisions are not made within the first few hours after admission), the following the first few hours after admission), the following protocol is recommended:protocol is recommended:

marker marker admission admission +6 h +6 h +12h +12h or next morning or next morning

cardiac troponin cardiac troponin X X X X XX

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 pts Median length of stay Median costTest group 4 days £ 910Control group 5 days £ 1125

Non-ischemic chest pain ptsTest group 2 days £ 235Control group 9 days £ 1125

“Control” indicates use of the traditional enzymatic approach.“Test” indicates use of cardiac troponin T protocol.

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

Question

How much necrosis is needed to make diagnosis of MI?

In the purest physiologic sense, any detectable necrosis is a MI.

Answer

Cardiac death or MI, %

Time from inclusion (days)

Troponin T, g/L

> 0.62< 0.62

< 0.18

< 0.06

160140120100806040200

48

121620

24

Lindahl B et al., 1996

FRISC-2 StudyFRISC-2 Study

Lindahl B et al., 2000

cTnT, g/L <0.01 0.01 <0.03 0.03 <0.10 0.10

n=541 n=1615 n=656 n=1500 n=892n=1264

12-m death, % 1.7 5.9 * 2.7 5.7 ** 3.4 5.9 **

12-m death/AMI, % 8.5 18.0 * 10.2 17.9 * 13.8 16.9ns

* P <0.001; ** P <0.01; ns = not significant

0.1 1 10

Morrow DA et al., Clin Chem 2000

Risk of Death or MI at 43 Days

Lower Risk Higher Risk

Immuno-1 2.2 (1.3 - 3.6)

ACS:180 2.8 (1.5 - 5.1)

RxL 3.0 (1.5 - 5.7)

RR (95% CI)

Baseline cTnI 0.10 g/L

0

5

10

15

20

Dea

th MI

D o

r M

I

Dea

th MI

D o

r M

I D

MI

D o

r M

I

cTnI Negative

cTnI Positive

Dimension RxL

ACS:180 Immuno 1

Even

ts (

%)

at

43 d

ays

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

“An increased value for cardiac

troponin should be defined as a

measurement exceeding the

99th percentile of a reference

control group.”

MYOCARDIAL INFARCTION REDEFINEDMYOCARDIAL INFARCTION REDEFINEDMYOCARDIAL INFARCTION REDEFINEDMYOCARDIAL INFARCTION REDEFINED

The Joint European Society of Cardiology/American College of Cardiology Committee, Sept 2000

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

Imprecision around the Diagnostic Cutoff of Troponin Assays

Assay Troponin,g/L CV,% Abbott AxSYM 2.90 10.0

Bayer ACS:180 1.33 4.1Bayer ACS:Centaur 0.52 13.0Bayer Immuno 1 1.00 4.9

Beckman Access 2nd gen. 0.09 10.0Biosite Triage 0.34 19.5

Dade Dimension RxL 2 gen. 0.14 11.4Dade Opus 2nd gen. 1.70 25.6Dade Stratus CS 0.08 14.0 BioMerieux Vidas 0.27 8.4DPC Immulite 1.00 9.8First Medical Alpha Dx 0.30 7.4Ortho-Clinical Diagn. Vitros 0.35 10.0Roche Cardiac Reader 0.33 18.0Roche Elecsys 3rd gen. 0.11 3.6

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.

0

10

20

30

40

0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.1

Cardiac troponin concentration

CV,

%

Assay AAssay B

99th URL

Implication of troponin assay imprecision for AMI diagnosis

Assay

Calculated

99th URL

(AMI cutoff)

Concentration associated

with a 10% CV

Abbott AxSYM 0.50 g/L 2.90g/L (5.8 x URL)

Bayer ACS:Centaur 0.15 g/L 1.40 g/L (9.3 x URL)

Dade Behring Dimension 0.05 g/L 0.40 g/L (8 x URL)

DPC Immulite 0.40 g/L 1.20 g/L (3 x URL)

Ortho Vitros 0.10 g/L 0.35 g/L (3.5 x URL)

Roche Elecsys 0.01 g/L 0.03 g/L (3 x URL)

Panteghini M, 2001

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.

Firenze, 10 ottobre 2001

Incontro Nazionale su “La nuova

definizione di infarto miocardico”

Obiettivo: ottimizzare l’uso dei marcatori di

danno miocardico attraverso il

raggiungimento di un consenso nei

comportamenti nella pratica clinica, anche

per favorire l’introduzione della nuova

definizione di IM