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Theresa JosephMedical Scientific Liaison

Roche Diagnostics

Natriuretic Peptides & Troponin:Testing Today

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• Your Name Here is an employee of Roche Diagnostics within the division of Medical Scientific Affairs.

• Data presented is intended for purely educational use to provide the participant with scientific, evidenced-based data in compliance with FDA guidelines.

All Trademarks, trade names, images, or logos mentioned or used herein are the property of their respective owners and are not used for purposes of promotion or as an indication of affiliation with

the provider of any particular good or service.

Disclosures

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Program Description

• This program is intended to familiarize health professionals and laboratorians with data supporting evidenced-based practice guidelines related to care of the patient with Acute Coronary Syndrome and/or Heart Failure.

• The Focus will be on diagnostic and prognostic value of troponin & natriuretic peptides.

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• Describe the biochemical and physiological effects of the

cardiac natriuretic peptide and troponin system.

• Identify biological and physiological factors for

consideration in the clinical application of natriuretic

peptide and troponin measurements in acute and chronic

disease settings

• Analyze evidenced-based clinical outcome data related to

the diagnostic and prognostic impact of natriuretic peptide

and troponin use in primary and acute care settings

Objectives

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Biology of the NP SystemSynthesis and Release

pre-proBNP 1-134

Meprin ABNP7-32

DPP-IVBNP3-32

proBNP 1-108

BNP1-32NT-proBNP 1-76

proBNP 1-108

Signal peptide(26 amino acids)

Kim & Januzzi. 2011. Circulation;123(18), 2015-2019

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B-Type Natriuretic Peptides

Characteristics BNP NT-proBNP

Size 32 Amino acids (AA) 76 AA

Half-life 20 minutes 60-120 minutes

StabilityUp to 4 hrs at room

temp.

Up to 3 days at room

temp.

ClearanceNP Receptor-C,

Endopeptidases, kidneyUnclear, possibly kidney

EMCREG International Newsletter, Dec. 2005, Vol. 6

Characteristic

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Natriuretic Peptides: Influences from cardiovascular/renal dysfunction, age, BMI

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Physiological ConditionsInfluence on Natriuretic Peptides Levels

Condition1,2,3

Effect on B-Type NP

Levels

Advancing age ↑↑↑↑Female gender ↑↑↑↑Obesity ↓↓↓↓Renal dysfunction ↑↑↑↑Valve disease ↑↑↑↑Atrial fibrillation ↑↑↑↑Left ventricular hypertrophy ↑↑↑↑Diastolic heart failure ↑↑↑↑Incompletely treated heart failure ↑↑↑↑

1. Hildebrandt P. In NT-proBNP as a biomarker in cardiovascular diseases. Bayers-Genis, Januzzi, eds. Prous Science: Barcelona; 2008. 2. Bayes-GenisA et al. Am J Cardiol. 2008;101(suppl):89A-94A. 3. DeFilippi C et al. Am J Cardiol. 2008;101(suppl):82A-88A.

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0

10

20

30

40

50

60

< 45 Y/O 45-54 Y/O 55-64 Y/O 65-74 Y/O 75+ Y/O

BNP

Analytical Considerations & Age Levels increase with age and have to be interpreted in clinical context

0

50

100

150

200

250

< 45 Y/O 45-54 Y/O 55-64 Y/O 65-74 Y/O 75+ Y/O

NT-proBNP

Mean results reported in pg/ml

Aggregate data from from FDA submission data in three BNP and two NT-proBNP package inserts. Advia package inserts Centaur BNP Package Insert 2008;

Biosite BNP Package Insert 2002; Abbott Axsym BNP Package Insert 2004; Roche NT-proBNP II Package Insert 2008; Ortho NT-BNP Package Insert Version 1.0 9

Analytical Considerations Natriuretic Peptide concentrations increase progressively as GFR decreases

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Austin et al. Am J Clin Pathol. 2006;126:506-512.

GFRGFRCKD 1CKD 1 CKD 2CKD 2 CKD 3CKD 3 CKD 4CKD 4 CKD 5CKD 5

GFRCKD 1 CKD 2 CKD 3 CKD 4 CKD 5

Influence of Natriuretic Peptide Concentrations By eGFR and Diagnosis of Decompensated Heart Failure

DeFilippi, C. et al.: ”Impact of Renal Disease on Natriuretic Peptide Testing for Diagnosing Decompensated Heart Failure

and Predicting Mortality.” Clin. Chem. 2007; 53: 1511-1519.

NT-proBNP BNP

Influence on Natriuretic Peptide LevelsRenal Disease

Anwaruddin, S. et al.: “ Renal Function, Congestive Heart Failure, and Amino-Terminal pro-Brain Natriuretic Peptide

Measurement Results From the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study.”

JACC 2006; 47:91-97.

NT-proBNP BNP

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Analytical Considerations Impact of body mass index (BMI) on Natriuretic Peptides

Krauser, D.G. et al.: “Effect of body mass index on natriuretic peptide levels in patients with acute congestive heart failure: A ProBNP Investigation of

Dyspnea in the Emergency Department (PRIDE) sub-study.” Am. Heart Journal 2005; 149: 744-750.

NT-proBNPNT-proBNP BNPBNPNT-proBNP BNP

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FDA Cleared Claims

Elecsys proBNP II Package Insert, version 2012.06, V5

NT-proBNP

• An aid in the diagnosis of individuals suspected of having

congestive heart failure

• For risk stratification in patients with ACS and CHF

• An aid in the assessment of increased risk of cardiovascular

events and mortality in patients at risk for heart failure who

have stable coronary artery disease.

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Utility of NT-proBNP in HF

HFAcute carePrimary care

Symptoms

Aid in Diagnosis of suspected HF Outcomes

PrognosisDiagnosis

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Clinical Performance Represented ROC CurveFDA cleared clinical thresholds to rule-out heart failure:

125 pg/ml for younger patients, 450 pg/ml for patients 75 years and older

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Receiver Operator Curve (ROC) Box and Whiskers Plot

Elecsys proBNP II Package Insert, version NT-pro 2012.06, V5

Clinical Utility Excluding Heart Failure

Elecsys proBNP II Package Insert, version NT-pro 2012.06, V5

Heart Failure Unlikely Additional CV assessment indicated

Patient

< 75 years > 125 pg/mL

Older patient

≥≥≥≥ 75 years > 450 pg/mL

NT-proBNP assay

Patients Suspected of Having HF

Patient

< 75 years < 125 pg/mL

Older patient

≥≥≥≥ 75 years < 450 pg/mL

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> 100 pg/mL

BNP assay

Heart Failure unlikely

Patients Suspected of Having HF

Additional CV assessment indicated

< 100 pg/mL

Aggregate data from FDA submission data in three BNP package inserts. Abbott Axsym BNP Package Insert February 2004, Biosite BNP Package Insert

2002, Advia Centaur BNP package Insert 2008

Clinical Utility BNP Excluding Heart Failure – Single Cut-Point

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• Different modes of degradation• Different half-lives• Different cut-offs

• General recommendations apply to both BNP and NT-proBNP • Individual values are NOT interchangeable

Are BNP and NT-proBNP Values Interchangeable?Basic Differences

Source: 1 Hall, C, Eur J Heart Fail (2004) 6 (3) 257-260, 2 Maisel et al, State of the Art Using NP Levels, Eur J Heart Failur (2008) 10, 824-839

NO!

1

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Demographics And Clinical Characteristics

Patients classified according to AHA/ACC heart failure classification scheme. Study included 86 health controls and 820 patients with HF in stages A-D. 479 patients had symptomatic heart failure in NYHA classes I-IV.

20Emdin, M. et al: “Comparison of Brain Natriuretic Peptide (BNP) and Amino-Terminal proBNP for Early

Diagnosis of Heart Failure.» Clin. Chem. 2007; 53:1289-1297.

Plasma Concentrations of BNP and NT-proBNP in healthy

controls and patients with heart failure in stages A-DConcentrations levels at 10th, 25th, 50th(median), 75th and 90th percentile, *: differences between groups are statistically significant with p<0.001 for all groups of comparison.

21Emdin, M. et al: “Comparison of Brain Natriuretic Peptide (BNP) and Amino-Terminal proBNP for Early

Diagnosis of Heart Failure.» Clin. Chem. 2007; 53:1289-1297.

A B C D

BNP, (ng/L) 11 (5–19) 20 (10–40) 165 (52–378) 404 (182–1012)

NT-proBNP, (ng/L) 43 (26–85) 88 (43–224) 1136 (379–2824) 4394 (1467–10 184)

Plasma Concentrations of BNP and NT-proBNP in healthy

controls and patients with HF in NYHA stages I-IVConcentrations levels at 10th, 25th, 50th(median), 75th and 90th percentile, *: differences between groups are statistically significant with p<0.001 for all groups of comparison.

22Emdin, M. et al: “Comparison of Brain Natriuretic Peptide (BNP) and Amino-Terminal proBNP for Early

Diagnosis of Heart Failure.» Clin. Chem. 2007; 53:1289-1297.

Influence on Natriuretic Peptide LevelsHeart Failure with Preserved Ejection Fraction (HFpEF)

O Donoghue, M. et al.: “The Effects of Ejection Fraction on N-Terminal ProBNP and BNP Levels in Patients With Acute CHF:

Analysis From the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study.”

Journal of Cardiac Failure 2005; 11 (5 Suppl.): S9-S14.

NT-proBNP BNP

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Heart muscle disease

Hypertrophic heart muscle

disease

Infiltrative myocardiopathies

Acute cardiomyopathies

Inflammatory

Valvular heart

disease

Aortic stenosis and regurgitation

Mitral stenosis and

regurgitation

Arrhythmia

Atrial Fibrillation

Atrial Flutter

Anemia Critical Illness

Bacterial sepsis

Burns

Adult respiratory

disease

StrokePulmonary

heart disease

Sleep Apnea

Pulmonary embolism

Pulmonary hypertension

Congenital heart disease

Does a Positive NT-proBNP Result Always Mean

“Heart Failure?”Non-Heart Failure causes of NTproBNP elevations: Possible Diagnosis

Baggish et al Differential of an Elevated Amino-Terminal Pro-B type Natriuretic Peptide Level, AJC, (2008) Vol. 101 (3A) 24

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Will the Natriuretic Peptide Numbers Always

Match the Clinical Picture?Key Points to Remember

Maisel et al, State of the Art Using NP Levels, Eur J Heart Failur (2008) 10, 824-839

+++ Important to look at the entire clinical picture+++

Chronic heart failure patients tend to have chronic ally elevated levels of both BNP and NT-proBNP

Helpful to identify the patient’s baseline NT-proBN P value and compare levels

Elevations should NOT be discarded without consider ation of adverse outcomes

Greatest value when complements clinical skills and other diagnostic tools

Not a stand alone test

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Use of Natriuretic Peptides Enhances Clinical Judgment

NT-proBNP BNP

Maisel, A. et al.: ” B-Type Natriuretic Peptide and Clinical Judgment in Emergency Diagnosis of Heart Failure An alysis From Breathing Not Properly (BNP) Multinational Stu dy.” Circulation 2002;106:416-422

Januzzi et al.: “The N-Terminal Pro-BNP Investigati on of Dyspnea in the Emergency Department (PRIDE) Study.” Am. Journal Cardiology 2005;95:948-954

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Risk Stratification of NT-proBNP in ER Setting

Januzzi, J.L. et al.: “Utility of Amino-Terminal Pro–Brain Natriuretic Peptide Testing for Prediction of 1-Year Mortality in Patients With Dyspnea Treated

in the Emergency Department.” Arch Intern Med. 2006;166:315-320

NT-proBNP predicts risk of death for both patient groups –

those with and without diagnosis of HF.

27 Fisher et al., N-terminal pro B type natriuretic peptide, but not the new putative cardiac hormone relaxin, predicts prognosis in patients with chronic

heart failure. Heart 2003; 89 (8):879-81

NT-proBNP below the median:Mortality = 11% (n = 5)

NT-proBNP above the median:Mortality = 53% (n = 23)

N = 87Range: 134 pg/ml - 35000 pg/mlMedian: 2994 pg/ml

Prognostic Value of Discharge NT-proBNP level on Mortality

Acute Risk AssessmentNT-proBNP Levels in the Assessment of Risk in Decompensated Heart Failure

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Acute Heart Failure In-hospital NT-proBNP risk stratification

Hospitalization-free survival (based on levels of NT-proBNP

.Bettencourt P et al. Circulation. 2004;110:2168-2174.

Hazard ratio (HR) = Relative likelihood of an event in one group

compared with another group at any point in time29

Cu

mu

lati

ve

pro

ba

bilit

y o

f d

ea

th (

%)

Days

Acute Coronary SyndromesElevated NT-proBNP and 1-year mortality

James SK et al. Circulation. 2003;108:275-281.30

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Acute Coronary SyndromesElevated NT-proBNP associated with myocardial infarction during 30-day follow-up

31James SK et al. Circulation. 2003;108:275-281.

2.7%

5.4% 5.7%

7.5%

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

Myocardial infarction rate

NT-proBNP concentration

> 1869 ng/L669-1869 ng/L238-668 ng/L≤≤≤≤ 237 ng/L

James SK et al. Circulation. 2003;108:275-281.

Acute Coronary SyndromesElevated NT-proBNP and 1-Year Mortality

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0

5

10

15

20

25

<= 237

237- 669

669- 1869

>1869

NT-proBNP,

quartiles pg/l

> 0.470.12 - 0.47

0.01 - 0.12<= 0.01

Troponin T,

quartiles ug/l

Mo

rta

lity

1 y

ea

r (%

)

Mortality and Subsequent Myocardial Infarction in

Patients With Unstable Coronary Artery Disease

James, et al. Circulation (2003); 108:275-8133 34

Troponin Testing

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Areas of Confusion…..

• Changing Definition of MI

• How to interpret results

• Ever evolving Troponin Assays

� Improved analytical precision

� Improved ability to detect smaller concentrations of

Troponin

� Different threshold values

� Detection of Troponin in patients not experiencing

classical MI symptoms

• When to order a Troponin level

� Good intentions may lead to unnecessary testing

Here and Now

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• Facilitate cTn Assay Understanding:

Educate Medical Staff (Clinicians, Nurses, Pharmacist,

etc.)

�Performance characteristics

�Threshold limits

� Interpretation of results

• Ischemic

• Non-ischemic

Interpretation of Troponin Elevations

“Laboratorians’ Call to Action”1

1Rollins, G. “New, Practical Guidance for Cardiac Troponin-How Can Laboratorians Help Physicians? Clinical Lab News 2013 39:1-

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Reduce the Confusion

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Barriers in Diagnosing ACSNon ACS Troponin Elevation

Goal:

The test results change treatment decisions

Clinical Questions

Does specific test result change clinical practice (e.g. admission, catheterization, antithrombotic therapy, early discharge, ICD replacement

Goal:

Independent association with outcomes

Improved prognosis / stratification beyond established tools

Clinical Questions

What are risks of CV death, SCD, MI, recurrent ischemia, HF, stent thrombosis

Goal:

Identify patients with disease

Exclude patients without disease

Clinical Questions

ACS versus non-ACS etiology

MI versus unstable angina

-Type I MI (spontaneous) vs.

-Type II MI (secondary)

Cardiac troponin’s role in patient assessmentClinical utility covers a wide range of clinical applications

Flowchart modified from Scirica BM Acute coronary syndrome: emerging tools for diagnosis and risk assessment. J Am Coll Cardiol. 2010; 55(14):1403-1415.

Aid in DiagnosisRisk StratificationClinical Implication

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Acute Coronary SyndromeGuideline Directed Utilization of Cardiac Troponin

� Troponin: Clinical Value� Cardiac-specific marker� Accurately identifies myocardial necrosis,

it does not inform as to the cause(s)� Most appropriate cardiac marker and

criterion to define acute myocardial infarction, according to AHA/ACC recommendations

� Conveys prognostic information incremental to clinical characteristics

� Risk stratification in patients with coronary artery disease

� Levels correlate to infarction size� Large diagnostic window

(2 hours – 15 days)

2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (Updating the2007 Guideline and Replacing the 2011 Focused Update). JACC 2012.60.645

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Troponin Structure

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• Troponin complex made up of 3 protein subunits attached to tropomyosin on the

actin filament

• Essential for the regulation of striated muscle contraction

• Calcium mediated • Troponin T and I have different isoforms that are coded by separate genes in

cardiac and in skeletal muscle

Morrow et al. “Cardiovascular Biomarkers, Pathophysiology and Disease Management”. Humana Press 2006: Chapter 1, pg 16.

Cardiac Muscle Contraction regulated by

Troponin Complex

Troponin I - Inhibitory protein modulating actin and myosin interaction

Troponin C – Calcium-binding subunit of the troponin complex

Troponin T – Binding protein attaching complex to Tropomyosin

Defining Myocardial Infarction

1959 • WHO develops a definition of AMI to track prevalence and prognosis

� Initially only clinical Symptoms and ECG changes were included with markers of myocardial necrosis as secondary criteria

• CK and CK-MB are the “gold standard” biomarkers for the definition of cardiac injury

• Troponin T Assay (Boehringer-Mannheim) & Troponin I Assay (Dade Behring) approved by FDA.

• Consensus committee statement of the Joint European Society of Cardiology and the American College of Cardiology (ESC/ACC) redefinition of MI; Implied that any necrosis in the setting of myocardial ischemia should be labeled as an MI. Cardiac Troponin T or I as the preferred Biomarker for diagnosis of MI.

• Global Task Force further refined the definition of MI and emphasized the different conditions which might lead to an MI

• The Third Universal Definition of MI2012

2000

1994-95

2007

Historical Perspective

Morrow, D.A. et al: “Cardiovascular Biomarkers, Pathophysiology and Disease Management”. Humana Press 2006: Chapter 3, pg 42.ESC/ACC 2000 Myocardial infarction redefined – a consensus document for the redefinition of myocardial infarction. JACC,2000; 36:959–969. Thygesen, K. et al.: Universal Definition of Myocardial Infarction. JACC 2007; 50: 273 – 295. ACC/AHA 2012 Third Universal Definition of Myocardial Infarction: JACC. 2012, Vol.60, No.16..

1971-86

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2012 Universal Definition of Myocardial Infarction

� Detection of a rise and/or fall of cardiac biomarkers

(preferably troponin) with at least 1 value above the

99th percentile reference limit together with evidence of

myocardial ischemia and at least 1 of the following:

• Ischemic symptoms

• ECG changes indicative of new ischemia

• Pathological Q waves

• Imaging evidence of new loss of viable myocardium or new regional

wall motion abnormality

• IC thrombus identified by angiography or autopsy

� Timing is essential, serial testing recommended

Thygesen et al: Universal Definition of Myocardial Infarction. Circulation 2012;126:2020-2035

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Interpretation of Troponin Elevations Thresholds / Cutoffs

• 97th Percentile

• 99th Percentile

• 10% CV

• 10% or 20% CV

Practical Considerations - Interpretation of Troponin

Elevations Evolving Universal Definition of Myocardial

Infarction: Thresholds

Adapted from Fox, Keith AA, “High Sensitivity Troponin, Strengths and Weaknesses”. Presented @ ESC Congress 26-08-2012.

Diagnosis of

MI“Normal”

Population”

99th centile

(Universal Definition)

4th generation

assay

3rd

generation

assay

WHO

definition

The 99th percentile of a health reference population is…

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Troponin T Elevations in the General Population

cTnT was undetectable among healthy subjects in the Dallas Heart Study

Wallace T.E. et al: Circ. 2006;113:1958-196546

Interpretation of troponin elevationsImportance of serial troponin sampling

Allows for differentiation of acute versus chronic troponin elevation

No agreement on what the absolute frequency of troponin testing should

be

• AHA Guidelines: baseline, 6 hours, and 12 hours1

• Universal Definition of MI: 0, 3, 6 hours2

Other Factors:

• Biological variation

• Defining criteria for a significant change

• Serial specimen collection improves identification of an acute event

1. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 Guidelines for the management of patients with unstable angina/non-ST-

elevation myocardial infarction. J Am Coll Cardiol. 2013;61(23):e179-347.2. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation. 2012;126(16):2020-2035.

Non ACS Troponin

Elevations

White et al., Clinical Implications of 3rd Definition of MI. Heart 2013.

Injury related to supply/demandOf myocardial ischemia

Injury not related to myocardial ischemia

Multifactorial or indeterminatemyocardial injury

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Release pattern of Troponin:Peak during 24 hrs Subsequent fall to undetectable levels

Prolonged release lengthens diagnostic window:

Troponin T:7 – 14 days

Troponin I:7 – 10 days

French, J.K. and White, H.D., Heart 2004; 90:99-106 ( Illustration) Sodi R., Advances in Clinical Chemistry 2006; 41;49-122.

Bertinchant JP et al. “Release kinetics of serum cardiac troponin I in ischemic myocardial injury”, Clin Biochem 1996; 29;587-594.

Kinetic Profiles of Cardiac Markers following MICardiac Troponin: Release Kinetics

49Modified from Mahajan VS, Jarolim P. How to interpret elevated cardiac troponin levels. Circulation. 2011;124:2350-2354.

Interpretation of troponin elevationsKinetic pattern of cardiac markers: rise and fall patterns

• Troponin levels are of value when they contribute to

accurate diagnosis or inform prognosis.

• Clinically useful Interpretation of Tn levels in:

• Chronic Kidney Disease (CKD)

• Heart Failure

• Pulmonary Embolism (PE)

• Chemotherapy-Associated Cardiac Toxicity

• Sepsis

Practical Considerations - Interpretation of Troponin

ElevationsNonischemic Cardiac Troponin Elevations

.

ACCF 2012 Expert Consensus Document on Practical Considerations in the Interpretation of Troponin Elevations: JACC. 2012, Vol.60, No.23.

� Aim: Assess Troponin concentrations in CKD patients not on dialysis

� Methods: N=222, follow-up 19 months, CKD Stages 3-5,

Echocardiogram

� Results:

• TnT levels above 99th Percentile in 43% of patients vs 18% with TnI

• TnT and TnI are more commonly increased in presence of more

severe CKD

• Decreasing GFR increased odds of having detectable TnT but not

TnI

• TnT is a marker of decreased survival

Abbas, N.A. et al: Clin Chem 2005: 51:11

Nonischemic Troponin ElevationsKidney Disease

“Cardiac Troponins and Renal Function in

Nondialysis Patients with Chronic Kidney Disease”

52

• TnT differed significantly between CKD stages ( p = <0.0001)

• Increased TnT associated with reduced eGFR

• OR 0.939 (CI 0.916 – 0.963) ( p = <0.001)

% c

Tn

Leve

l>9

9%

0%

10%

20%

30%

40%

50%

60%

CKD 3 CKD 4 CKD 5

TnTTn I

20%

11%

39%

12%

59%

26%

Abbas. (2005). Clin Chem. 51(11)

Percentage of Patient exceeding > 99 th Percentile Tn level as compared by CHD Stage

“Cardiac Troponins and Renal Function in

Nondialysis Patients with Chronic Kidney Disease”

• TnI differed significantly between CKD stages 4 & 5 ( p = 0.0197) But not between CKD stages 3 & 4.

• Increased TnI associated with reduced eGFR

– OR 0.961 (CI 0.931 – 0.992) ( p = 0.015)

CKD 3 (GFR <60-30)CKD 4 (GFR 29-15)CKD 5 (GFR <15 or “ON DIALYSIS”)

�Conclusions:

• TnT and TnI elevations are common in pre-dialysis CKD patients, without ACS

• Detectable TnT was marker of decreased survival

Nonischemic Troponin ElevationsKidney Disease

53

cT

n L

ev

el

>9

9%

TnI-Ultra did not differ significantly between CKD stages ( p = 0.6)

A sensitive assay shows TnI concentrations to be more prevalent in pts with CKD than previously believed

TnI levels increase in approximately 1/3 of predialysis patients

Lamb EJ, Kenny C, Abbas NA, et al. Cardiac troponin I concentration is

commonly increased in nondialysis patients with CKD: experience with a sensitive assay. Am J Kidney Dis 2007;49(4);507-516.

Nonischemic troponin elevationsKidney disease

Percentage of patients exceeding >99th percentile Tn level as compared by CKD stage

CKD 3 (GFR <60-30)CKD 4 (GFR 29-15)CKD 5 (GFR <15 or “ON DIALYSIS”)

“Cardiac Troponin I Concentration is Commonly Increased in Nondialysis Patients with CKD:

Experience with a Sensitive Assay”

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Morrow, D.A. et al: “Cardiovascular Biomarkers, Pathophysiology and Disease Management”. Humana Press 2006: Chapter 10, pg 141,145-149.

Practical Considerations – Nonischemic Troponin ElevationsDetectable Levels of Troponin are Prognostic

CHF

Pulmonary Edema

Sepsis During ICU Stay

Non-Cardiac, Critically ill ED Patients

Acute Stroke

Postoperative Vascular Surgery

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Practical Considerations - Interpretation of Troponin

Elevations Thresholds / Cutoffs

• 97th Percentile

• 99th Percentile

• 10% CV

• 10% or 20% CV

Apple, F.S. and P.O Collinson: Clin. Chem. 2012; 58: 54-62.

Practical Considerations - Interpretation of Troponin ElevationsAnalytical Characteristics Contemporary Troponin Assays

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TroponinLinking Your Lab to Clinical Decision Making

Differential diagnosis of acute coronary syndrome to identify cell

necrosis as seen in acute myocardial infarction

Risk stratification of patients presenting with acute coronary

syndrome

Determining cardiac risk in patients with chronic renal failure

Selection of more intensive therapy and intervention in patients

with elevated levels of cardiac troponin T

Commercially available cardiac troponin T

test is FDA-cleared for:

Troponin T STAT [package insert]. 2012-07, V7. Indianapolis, IN: Roche Diagnostics Corporation; 2012.

59

Clinical Performance Data Derived From

Sub-Studies Of 3 Major Clinical Trials

60

• FRISC II investigators: “Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomized multicenter study.”Lancet 1999; 354: 708-715

• 3,048 patients

• TACTICS TIMI 18 Trial: Cannon, C.P. et al.: “Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor Tirofiban.” NEJM 2001; 344: 1879-87

• 2,220 patients

• GUSTO IV investigators: “Effect of glycoprotein IIb/IIIa receptor blocker abciximabon outcome in patients with ACS without early coronary revascularization: The GUSTO IV - ACS randomized trial.” Lancet 2001; 357: 1915-1924

• 7,600 patients

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Verification of FRICS II findings in GUSTO IV

James, S.K. et al: Am J Med 2003; 115: 178- 184

Sensitivity of Troponin T for Detection of Death and MI at 30 Days in FRISC II and GUSTO IV

Below Cutoff Above Cutoff

61

Risk Stratification in ACS Patients

Per

cent

age

James, S.K. et al: Am J Med 2003; 115: 178- 184

22

# Patients/group 1,992 571 873 3,679

Evaluated Cutoff Points for Troponin T

30 Day risk of Death or MI in the GUSTO IV Trial

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Extent of CAD in FRISC IIElevated troponin levels and ECG changes reflect multi-vessel disease

0

5

10

15

20

25

30

35

40

45

50

No ST dep ST dep No ST dep ST dep

0 - VD

1 - VD

2 - VD

3 - VD/LM

n = 223 n = 149 n = 391 n = 357

Troponin T < 0.03µ/L Troponin T ≥ 0.03µ/L

Diderholm, E. et al.: Am Heart J. 2002; 143: 760-767.

%

63

TACTICS TIMI 18 and Clinical Implications

Endpoints

• At 30 days

• TnT > 0.01*

• Primary endpoint

• Death/non-fatal MI

• TnT ≤ 0.01*

• Primary endpoint

• Death/non-fatal MI

Invasive

506

40 (7.9%)

27 (5.3%)

414

25 (6.0%)

12 (2.9%)

Non-invasive

480

78 (16.2%)

51 (10.6%)

426

24 (5.6%)

13 (3.1%)

Odds Ratio

(95% CI)

0.44 (0.30-0.66)0.47 (0.29-0.77)

1.08 (0.60-1.92)0.95 (0.43-2.10)

P

<0.0010.002

0.800.90

Cannon, C.P. et al.: NEJM 2001; 344: 1879-87

47% Reduction in Death and MI at 30 days

64*Troponin measured in ng/mL

• Both TnT and TnI are cardiac specific antigens

• Troponin assays are not the same. They should be

treated as different analytes

• Clinical utilities reported in literature are not

applicable to every troponin assay

• No correlation among different TnI assays can be

expected unless they use the same antibody pairs

• Core lab and POCT assays should use the same

antibodies to ensure agreement in results.

65

Points to Consider When Discussing Troponin Assays

ACCF 2012_Newby et al_ Expert Consensus Document on Practical Considerations in the Interpretation of Troponin Elevations: JACC. 2012, Vol.60, No.23.

• Practice Guidelines play a key role in the diagnosis and

management of both Heart Failure and ACS

• Troponin and Natriuretic Peptides play a crucial role in

the aid in diagnosis and prognosis of these disease

processes

• Individually Troponin and Natriuretic Peptides provide

diagnostic and risk stratification information for

patients with Acute Coronary Syndrome and Heart Failure

in both the acute and chronic setting

• Troponin and Natriuretic Peptide levels are not stand-

alone tests. It is always of greatest value when they

complement the clinician’s clinical skills along with other

available diagnostic tools.

Natriuretic Peptide and Troponin TestingConclusions

66