Mario Plebani University-Hospital of Padova, Italy

CK-MB mass assay CHF guidelines use BNP for rule out AST in AMI CK in AMI INH for CK-MB electrophoresis for CK and LD isoenzymes RIA for myoglobin WHO criteria for AMI ctnt assay ctni assay POCT for BNP IRMA for BNP AMI redefined Markers of ischemia and plaque destabilization ECLIA for NT-proBNP 1950 1960 1970 1980 1990 2000 2010

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:

Diagnosis 2011

1 Criterion 2 Criterion Apple FS. Clin Chem, 2009

1. First, an improved diagnostic accuracy, mainly in patients presenting early after the onset of symptoms, 2. A high-diagnostic accuracy in patients who are troponin-negative with the contemporary assay(s); 3. An incremental prognostic value, allowing improved risk stratification. 4. No need for other biomarkers, including early markers

UA AMI Wilson SR et al., Am Heart J. 2009

2. A high-diagnostic accuracy in patients who are troponin-negative with the contemporary 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, allowing improved risk stratification.

Korley F et al, 2014

The new high-sensitivity troponin methods allow detection of very minor damages of the heart muscle increasing numbers of patients with elevated troponin concentrations and thus hamper interpretation of troponin results. Agewall S et al. Eur Heart J 2011

Melanson S, Circulation 2007

Clinical assessment, 12-lead electrocardiography (ECG) and measurement of cardiac troponin levels form the pillars for the early diagnosis of acute MI in the emergency department (ED).

2015 ESC Guidelines for the management of ACS

RAPID RULE-OUT Biomarkerbased strategies 3h: ESC 2011 algorithm 2h:2h-Advanced diagnostic protocol and 2h-algorithm 1h: 1h-algorithm 0h: dual-marker Strategy (ctn+ copeptin) 0h: undetectable Hs ctn

ctn in the normal range at presentation and at 3h and if the patients fulfils 2 additional requirements: 1) to be pain-free; 2) to have a GRACE-SCORE <140 In patients presenting more than 6h after chest pain onset a single blood draw at presentation is sufficient

2015 ESC Guidelines for the management of ACS

Keller et al. N Engl J Med 2009

ADP protocol combines the TIMI-score with ECG and hs-ctn assay at 0 and 2h (both should be normal) 2h-algorithm uses exclusively hs-ctn assays

NPV: 99.5% PPV: 85% Reichlin T et al. Am J Med 2015

The combination provides incremental diagnostic value only when using conventional ctn assays (NPV 98-99%) Major limitation: the complexity to add an additional analyzer into the laboratory workflow

Mueller C, Plebani M et al, in press

Exclusively based on hs-ctn concentrations at presentation and at 1h (absolute change) Rapid rule-out of AMI in up to 60% of chest pain patients

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 a very high NPV (98-100%) for AMI

Hs-cTnT below LOD at admission Rubini Giménez et al. Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin. Int J Cardiol. 2013

Undetectable hs-ctnt levels (< 5 ng/l) have a NPV 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 : 98.1 to 100%)

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

A first hs-ctnt level < 5 ng/l in combination with no sign of ischemia (ECG) has a NPV for MI of 99.8% (95% CI: 99.7 to 99.9) and An absolute risk for MI of 0.17% (95% CI: 0.09 to 0.27) 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 alternative causes of chest pain More rapid discontinuation of rhythm monitoring

RULE-IN STRATEGIES The ESC 2011 Guideline hs-ctn time 0 and after 3h (at least 1 value> 99th + rising/fall) ABSOLUTE DELTA CHANGES RELATIVE AND DIFFERENT DELTA (optimal cut-off?) PPV= 84% PPV= 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-ctnt 1,2,6 (Elecsys) hs-ctni 3,7 (Architect) hs-ctni 4 (Dimension Vista) s-ctni ultra 5 (Centaur) Hs-cTnT 52 OR 1h delta 5 Hs-cTnI 52 OR 1h delta 6 Hs-cTnI 107 OR 1h delta 19 s-ctni 166 OR 1h delta 30 Validation +++ +++ Additional advantages Also provides guidance for rule-out Hs-cTnT 53 OR 1h delta 10 Hs-cTnI 64 OR 1h delta 15 s-ctni 166 OR 1h delta 36 Also provides guidance for rule-out

The PPV for MI with previously described strategies was 75-80%. Most of the rule-in patients with diagnoses other than MI did have conditions that usually require inpatient coronary angiography for accurate diagnosis, including Taki-Tsubo cardiomyopathy, 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 for determining 99 percentile Gender-specific cut-offs Biomarkers after percutaneous coronary intervention Biomarkers in the setting of chronic kidney disease Standardization and harmonization

Shah AS et al BMJ 2015

Use of sex-specific thresholds doubled the rate of diagnosis in females (11% to 22%), but had minimal effect on males (19% to 21%) Women with small increases in troponin concentration, only detectable using the sexspecific threshold, had rates of death or reinfarction that were comparable to or worse than women with much larger infarcts identified using the clinical assay. Shah AS et al BMJ 2015

Natriuretic peptides testing revolutionized HF care by: facilitating earlier and more secure diagnosis; rapid rule-out of acute HF in patients evaluated for acute dyspnea; assisting in gauging severity of HF; representing a prognostic gold standard in the diagnosis; 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