Mario PlebaniUniversity-Hospital

of Padova, Italy

1950 1960 1970 1980 1990 2000 2010

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

assay

cTnI

assay

IRMA

for BNP

POCT

for BNP

AMI

redefined

CHF guidelines

use BNP for

rule out

ECLIA for

NT-proBNP

Markers of

ischemia

and plaque

destabilization

Cardiac Biomarkers: past, present and future

…..troponin measurement performed alone is sufficient and that the measurement of additional markers does not significantly improve diagnostic efficiency beyond the measurement of

troponin alone.

Panteghini M et al. Clin Chem 2004

Salient features include:

2011

Diagnosis

Apple FS. Clin Chem, 2009

1° Criterion

2° Criterion

1. First, an improved diagnostic accuracy, mainlyin patients presenting early after the onset ofsymptoms,

2. A high-diagnostic accuracy in patients who aretroponin-negative with the contemporaryassay(s);

3. An incremental prognostic value, allowingimproved risk stratification.

4. No need for other biomarkers, including “earlymarkers”

Wilson SR et al., Am Heart J. 2009

AMI

UA

2. A high-diagnostic accuracy in patients whoare troponin-negative with thecontemporary assay(s).

Keller T et al., N Engl J Med 2009

Reichlin T et al. N Engl J Med 2009

Biomarkers

2011

3. An incremental prognostic value, allowingimproved risk stratification.

Korley F et al, 2014

• The new high-sensitivity troponin methodsallow detection of very minor damages of theheart muscle increasing numbers of patientswith elevated troponin concentrations andthus hamper interpretation of troponinresults.

Agewall S et al. Eur Heart J 2011

Melanson S,Circulation 2007

Clinical assessment, 12-leadelectrocardiography (ECG) andmeasurement of cardiac troponin levelsform the pillars for the early diagnosis ofacute MI in the emergency department (ED).

2015 ESC Guidelines for the management of ACS

2015 ESC Guidelines for the management of ACS

RAPID RULE-OUTBiomarker-

basedstrategies

3h: ESC 2011 algorithm

2h:2h-Advanceddiagnostic

protocol and2h-algorithm

1h: 1h-algorithm0h: dual-marker

Strategy(cTn+ copeptin)

0h: undetectable

Hs cTn

• cTn in the normal range at presentation and at3h and if the patients fulfils 2 additionalrequirements: 1) to be pain-free; 2) to have aGRACE-SCORE <140

• In patients presenting more than 6h afterchest pain onset a single blood draw atpresentation is sufficient

2015 ESC Guidelines for the management of ACS

Keller et al. N Engl J Med 2009

• ADP protocol combines the TIMI-score withECG and hs-cTn assay at 0 and 2h (both shouldbe normal)

• 2h-algorithm uses exclusively hs-cTn assays

NPV: 99.5% PPV: 85%

Reichlin T et al. Am J Med 2015

• The combination provides incrementaldiagnostic value only when using conventionalcTn assays (NPV 98-99%)

• Major limitation: the complexity to add anadditional analyzer into the laboratory work-flow

Mueller C, Plebani M et al, in press

• Exclusively based on hs-cTn concentrations atpresentation and at 1h (absolute change)

• Rapid rule-out of AMI in up to 60% of chest painpatients

One-Hour Rule-out and Rule-in of Acute

Myocardial Infarction Using High-Sensitivity

Cardiac Troponin T

Reichlin T et al. Arch Intern Med. 2012

• Undetectable hs-cTn at presentation has avery high NPV (98-100%) for AMI

Rubini Giménez et al. Rapid rule out of acute myocardial

infarction using undetectable levels of high-sensitivity

cardiac troponin. Int J Cardiol. 2013

Hs-cTnT below LOD at admission

Undetectable hs-cTnT levels (< 5 ng/L) have aNPV of 98.6% (95% CI 97.0 to 99.3%)

Undetectable hs-cTnI (Abbott) levels

(< 1.9 ng/L) have a NPV of 100% (95% CI : 98.1to 100%)

Bandstein et al. J Am Coll Cardiol 2014;63:2569-78.

•Bandstein et al. J Am Coll Cardiol 2014;63:2569-78.

A first hs-cTnT level < 5 ng/L in combination withno sign of ischemia (ECG) has a NPV for MI of99.8% (95% CI: 99.7 to 99.9)

and

An absolute risk for MI of 0.17% (95% CI: 0.09 to0.27)

and

a NPV for death within 30 days of 100%

Medical implications of accelerated rule-out:

More rapid relief of patient anxiety

More rapid indentification of alternativecauses of chest pain

More rapid discontinuation of rhythmmonitoring

RULE-IN

STRATEGIES

The ESC 2011 Guideline

hs-cTn time 0and after 3h

(at least 1 value> 99th+ rising/fall)

ABSOLUTE DELTA

CHANGES(optimal cut-off?)

PPV= 84%

RELATIVE AND DIFFERENT

DELTAPPV= 95.8%

One-Hour Rule-out and Rule-in of Acute Myocardial

Infarction Using High-Sensitivity Cardiac Troponin T

Reichlin T et al. Arch Intern Med. 2012

0h/1h-algorithm 0h/2h-algorithm

Setting ED ED

Specificity for AMI 95-97% 97-99%%

PPV for AMI 70-81% 77-85%

% ruled-in* 12-16% 8-14%

Characteristics if using:**hs-cTnT1,2,6

(Elecsys)

hs-cTnI3,7

(Architect)

hs-cTnI4

(Dimension Vista)

s-cTnI ultra5

(Centaur)

Hs-cTnT ≥52OR1h delta ≥5

Hs-cTnI ≥52OR 1h delta ≥6

Hs-cTnI ≥107OR 1h delta ≥19

s-cTnI ≥166OR1h delta ≥30

Hs-cTnT ≥53OR1h delta ≥10

Hs-cTnI ≥64OR 1h delta ≥15

s-cTnI ≥166OR1h delta ≥36

Validation +++ +++

Additional advantages Also provides guidance for rule-out

Also provides guidance for rule-out

• The PPV for MI with previously describedstrategies was 75-80%.

• Most of the “rule-in” patients with diagnosesother than MI did have conditions that usuallyrequire inpatient coronary angiography foraccurate diagnosis, including Taki-Tsubocardiomyopathy, myocarditis.

Accelerated rule-in implications:

• More rapid initiation of antiplatelet,anticoagulant and anti-ischemic medication

• More rapid transfer to coronary angiography

• Coronary revascularization, if feasible

• Defining healthy reference population fordetermining 99° percentile

• Gender-specific cut-offs

• Biomarkers after percutaneous coronaryintervention

• Biomarkers in the setting of chronic kidneydisease

• Standardization and harmonization

Shah AS et al BMJ 2015

• Use of sex-specific thresholds doubled the rateof diagnosis in females (11% to 22%), but hadminimal effect on males (19% to 21%)

• Women with small increases in troponinconcentration, only detectable using the sex-specific threshold, had rates of death orreinfarction that were comparable to or worsethan women with much larger infarcts identifiedusing the clinical assay.

Shah AS et al BMJ 2015

Natriuretic peptides testing revolutionized HFcare by:

– facilitating earlier and more secure diagnosis;

– rapid rule-out of acute HF in patients evaluatedfor acute dyspnea;

– assisting in gauging severity of HF;

– representing a prognostic gold standard in thediagnosis;

– providing a potential guide for HF therapy.

CRUSADE Study 5325 patients with NSTEMI-ACS

Mortality

Risk in H

Cullen LA et al. Clin Chem 2017

Jaffe A, Januzzi JL Clin Chem 2017