Troponin Testing Today - ASCLS - MOascls-mo.org/documents/Spring Meeting/Presentation...

Jen Quaglia BSN, RNMedical Scientific LiaisonRoche Diagnostics

Troponin Testing Today

1

• Jen Quaglia BSN, RN 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

2

• Describe the biochemical and physiological effects of

the cardiac troponin system

• Identify biological and physiological factors for

consideration in the clinical application of troponin

measurements in acute and chronic disease settings

• Analyze evidenced-based clinical outcome data related

to the diagnostic and prognostic impact of troponin use

in primary and acute care settings

Objectives

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The Troponin Complex

• Troponin I & T are not interchangeable

• Troponin I and I are not interchangeable

• Point of Care Troponin I is not interchangeable with Central Lab Troponin

T

5

Cardiac Troponin Subunits in Circulation

• Cardiac Myocyte

– Bound-Pool

– Free Pool

TnT ~6-8 %

TnI ~3-4 %

• Circulation

– Free form release of TnT and TnI

– T-I-C complex dissociation and degradation

• Binary I-C: Predominant form

• Free TnT

• Subunits

Release patterns of cardiac troponin found in circulation after myocyte necrosis

Januzzi, J.L. et al: “Cardiac Biomarkers in Clinical Practice”. Jones and Bartlett Publishers 2011; Chapter 1, pg 4.

Freda et al., J. Am Coll Cardiol 2002; 40:2065 (Modified Illustration)

Circulation

6


• Cardiac Myocyte

– Bound-Pool

– Free Pool

TnT ~6-8 %

TnI ~3-4 %

• Circulation

– Free form release of TnT

and TnI



• Free TnT

• Subunits


Circulation



7


• Cardiac Myocyte

– Bound-Pool

– Free Pool

TnT ~6-8 %

TnI ~3-4 %

• Circulation

– Free form release of TnT and TnI



• Free TnT

• Subunits


Circulation



8

Cardiac Troponin Detection

Amino acid 1

125 131 136 147

288

Epitope

M7 M11-7

30 110

211

Affinity for Proteolysis

Central Stable Area

Roche Elecsys and Cobas Troponin T Package Insert. 2010-08 V6

Sodi R., Advances in Clinical Chemistry 2006; 41;49-122.Katrukha, AG et al., 1998 Clin Chem 44(12);2433-2440 www.ifcc.org/index.asp/Scientific_Activities/SD_Committees/Standardisation of Markers of Cardiac Damage; “Troponin Assay Analytical Characteristics”

September 2009 version

Cardiac Troponin T

N C

Epitope Binding Sites

Affinity for Proteolysis

Amino acid 1

N C

Cardiac Troponin I

Antibody/epitope site selection

Single Manufacturer Multiple Manufacturers

N-terminal region Stable Area Affinity for

Proteolysis

9

Troponin Assay Analytical Variability

Adapted from: www.ifcc.org/index.asp/Scientific_Activities/SD_Committees/Standardisation of Markers of Cardiac Damage;

“Troponin Assay Analytical Characteristics” September 2009 version

IFCC : Analytical characteristics of commercial cardiac troponin I and T assays

per Manufacturer

Tro

po

nin

ch

an

ge

(%

)

0 200 400 600 800 1,000 1,200 1,400 1,600 1,800

Hemolysis index

cTnT: false negatives

180

120

60

0

-20

-40

-60

cTnI: false positives

Effects of Hemolysis on cTn

Bais, Clin Chem 2010; 56: 1357-9

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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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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 MI

2012

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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3rd 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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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:









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Point #1: Rise and/or Fall of Biomarkers (cTn)

Jaffe et al., J Am Coll Cardiol; 2006;48:1-11.

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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:









17

Point #2: Use of the 99th PercentileHow sensitive do Troponin assays really need to be?

• Requirement of troponin assays:

• Aid in diagnosing patients with AMI as early as possible

• Identify patients at risk of premature death from CVD

• To do this accurately, assays require acceptable precision

within the normal range

• Quantitate a high percentage of normal subjects

• Keep interferences minimal (hemolysis, heterophile Abs)

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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

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gen = generation; hs = high sensitivity

Apple, FS Clin Chem 2009; 55(7):1303-6

Cardiac Troponin Assay Scorecard

Acceptance Designation Total Precision at 99th Percentile

Guideline Acceptable < 10%

Clinically Usable >10 to < 20%

Not Acceptable > 20%

Assay Designation Measurable Normal Values Below the 99th Percentile

Level 4

3rd gen hs

> 95%

Level 3

2nd gen hs

75 to < 95%

Level 2

1st gen hs

50 to <75%

Level 1

Contemporary

<50%

19

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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








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MIM

Acute cTn elevation (with rise and/or fall

in cTn over serial measurement)

Myocardial

Injury

MyocardialInfarction

Point #3: Serial Sampling Increases SpecificityAcute and chronic release of cardiac Troponin

Thygesen K et al.. ESC/ACCF/AHA/WHF Task Force J Am Coll Cardiol 2012; 60(16):1581-98. & Eur Heart J 2012; 33:2551–67

Chronic cTn elevation (no acute changes)

Renal

failure

Non-cardiac

major procedure

Cardiac

procedure

Heart

failure

Tachy-/brady-

arrhythmia

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Modified from Mahajan, V.S. et al.: “How to Interpret Elevated Cardiac Troponin Levels”. Circulation. 2011;124:2350-2354.

Interpretation of Troponin ElevationsKinetic pattern of cardiac markers: rise and fall pattern

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2014 NSTE-ACS Management GuidelinesRecommendations for use of cardiac biomarkers

Amsterdam, E., et al, 2014 AHA_ACC Guideline for the Mgmt of Pts with NSTEMI ACS, Circulation 2014

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25



26

2014 AHA/ACC NSTE-ACS Guidelines:

0, and 3 – 6 hours1

Universal Definition of MI:

0, 3, 6 hours2

1. Amsterdam, E., et al, 2014 AHA_ACC Guideline for the Mgmt of Pts with NSTEMI ACS, Circulation 2014

2. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60(16):1581-

1598.

Guidelines and Guidance DocumentsRecommended frequency of troponin testing

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Emphasis on assessment of serial cTn changes:

• Required: cTn value above the 99th percentile of the URL

• Evidence for an acute increase or decrease ≥20% isrequired if the initial value is elevated

2014 NSTE-ACS Management Guidelines


Diagnosis

• 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)

Risk Stratification

• Goal:•Independent association with outcomes

•Improved prognosis / stratification beyond est. tools

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

Clinical Implication

• Goal:•The test results changes treatment decisions

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

Flowchart modified from Scirica, JACC 2010; 55 (14): 1403

Cardiac Troponin’s Role In Patient Assessment

Clinical utility covers a wide range of clinical applications

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Serial Troponin Values Grouped by Final Diagnosis

Troponin T – 0 hours

Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med. 2009;361(9):868-877.

Troponin T – 3 hours

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Diagnostic Accuracy 3 Hours After Admission

Troponin T

Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med. 2009;361(9):868-877.

Risk Stratification in ACS PatientsP

erc

en

tag

e

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

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# 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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Cannon CP, Weintraub WS, Demopoulos LA 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: 1879-1887.

TACTICS TIMI 18 and Clinical Implications50% reduction in death and MI at 30 days

TnT > 0.01 ng/ml TnT ≤ 0.01 ng/ml

• 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

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.

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

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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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 survivalAbbas, 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”

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• 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

Le

ve

l>

99%

0%

10%

20%

30%

40%

50%

60%

CKD 3 CKD 4 CKD 5

TnT

Tn I

20%

11%

39%

12%

59%

26%

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

Percentage of Patient exceeding > 99th 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

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• Guidelines play a key role in the management ACS

• Troponins play a crucial role in the aid of diagnosis and prognosis

• Troponin levels are not stand-alone tests

• Both TnT and TnI are cardiac specific antigens

• No correlation among different TnI assays can be

expected unless they use the same antibody pairs

Troponin TestingConclusions

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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”

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

39:1-4

Reduce the Confusion

• Describe the biochemical and physiological effects of

the cardiac troponin system

• Identify biological and physiological factors for

consideration in the clinical application of troponin

measurements in acute and chronic disease settings

• Analyze evidenced-based clinical outcome data related

to the diagnostic and prognostic impact of troponin use

in primary and acute care settings

Objectives

39

Troponin Testing Today - ASCLS - MOascls-mo.org/documents/Spring Meeting/Presentation...

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