Impact of high-sensitivity

Troponins (T and I)

Stewart Mann

UoW/CCDHB

Cardiac Biomarkers HistoryCardiac Biomarkers History

AST, angiotensin sensitivity test; CK, creatine kinase; INH, immunoassay; LD, lactate dehydrogenase

Why do we need a more sensitive cardiac biomarker?

Universal Definition of Acute MyocardialUniversal Definition of Acute Myocardial Infarction InfarctionThe ESC-ACC-AHA-WHF CriteriaThe ESC-ACC-AHA-WHF Criteria

Detection of Detection of rise and/or fallrise and/or fall of cardiac biomarkers (preferably troponin) of cardiac biomarkers (preferably troponin) with with at least one value above the 99at least one value above the 99th percentile percentile of the upper reference of the upper reference limit together with evidence of ischemia with at least one of the followinglimit together with evidence of ischemia with at least one of the following

Symptoms of ischemiaSymptoms of ischemia

ECG changes of new ischemia (new ST-T changes or new LBBB)ECG changes of new ischemia (new ST-T changes or new LBBB)

Development of pathologic Q waves Development of pathologic Q waves

Imaging evidence of new loss of viable myocardium or new regional Imaging evidence of new loss of viable myocardium or new regional wall motion abnormalitywall motion abnormality

Thygesen, Alpert, White. Universal DefinitionThygesen, Alpert, White. Universal Definition of Myocardial Infarction 2007 EHJ, JACC, CIRC of Myocardial Infarction 2007 EHJ, JACC, CIRC

Clinical Classification of different Clinical Classification of different Types of Myocardial InfarctionTypes of Myocardial Infarction

Type 1Type 1 Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as plaque erosion or rupture

Type 2Type 2 Myocardial infarction secondary to ischemia due to imbalance between

oxygen demand and supply e.g. coronary spasm            Type 3Type 3 Sudden cardiac death with symptoms of myocardial ischemia,

accompanied by new ST elevation or LBBB, or verified coronary thrombus by angiography, but death occurring before blood samples could be obtained

Type 4aType 4a Myocardial infarction associated with PCIType 4bType 4b Myocardial infarction associated with stent thrombosis

Type 5Type 5 Myocardial infarction associated with CABG

Thygesen, Alpert, White. Universal DefinitionThygesen, Alpert, White. Universal Definition of Myocardial Infarction 2007 EHJ, JACC, CIRC of Myocardial Infarction 2007 EHJ, JACC, CIRC

NACB and IFCC Guidelines for NACB and IFCC Guidelines for cardiac biomarkerscardiac biomarkers

Reference decision-limits should be established for each Reference decision-limits should be established for each cardiac biomarker on a population of normal, healthy cardiac biomarker on a population of normal, healthy individuals without a known history of heart disease individuals without a known history of heart disease (reference population)(reference population)

For cardiac troponin aFor cardiac troponin an increased value should be defined n increased value should be defined as a measurement exceeding the 99as a measurement exceeding the 99 thth percentile of a percentile of a reference control groupreference control group

Acceptable imprecision at the 99Acceptable imprecision at the 99 thth percentile for each percentile for each assay is defined as assay is defined as ≤ 10% coefficient of variation

Apple F et al. NACB Practice Guidelines in ACS; Circulation 2007, 352-355

TnT4G & hsTnT specifications

TnT

4th generation

TnT-hs

LoD Analytical sens

0.01 ng/ml

0.003 ng/ml

range 0.01 - 25 ng/ml 0.003 -10 ng/ml

99th percentile < 0.01 ng/ml < 0.014 ng/ml

LoQ (10%

CV)

0.03 ng/ml 0.013 ng/ml

UNITS

Current 0.03 limit is in ng/ml = 0.03 μg/l

= 30 ng/l = 30 pg/ml PROPOSED CHANGE:

use ng/l when hsTnT adopted threshold for ‘elevation’ (99th percentile) at 14 ng/l (0.014 ng/ml)

High sensitivity Troponin T assay

Correlation between hsTnT and TnT4G is excellent Correlation between hsTnT and TnT4G is excellent but intercept up to 23 ng/l (higher for hsTnT)but intercept up to 23 ng/l (higher for hsTnT)

Will replace current 4Will replace current 4thth generation test generation test

No additional costNo additional cost

Will fulfil the International requirements of 99Will fulfil the International requirements of 99 thth percentile and 10% CVpercentile and 10% CV

Jarausch Clinc Chem 2008; 54: B133

WRH Lab comparison of hsTnT to 4th generation TnT

Intercept : 9.762 [ 8.204 to 12.356 ]Slope : 0.943 [ 0.874 to 1.008 ]

Passing-Bablok agreement test N = 00 20 40 60 80 100 120

TNT0

20

40

60

80

100

120 hs-TNT

n=41

hsTnT=0.943 TnT(4g) +9.8 ng/L

r=0.975

Range (hs-TnT) 18-112 ng/L

Introduction of High Sensitivity Introduction of High Sensitivity Troponins: Implications for Troponins: Implications for clinical practiceclinical practice

Improved diagnosis of ACSImproved diagnosis of ACS Improved risk stratification in ACSImproved risk stratification in ACS

Improved risk stratification in non-ACSImproved risk stratification in non-ACS Monitoring of antimitotics e.g. herceptin?Monitoring of antimitotics e.g. herceptin?

Clinical decision points influenced by cardiac biomarkers

In a likely ACS Admit or discharge (i.e. diagnose an MI) Undertake further investigation for ischaemia Institute long-term preventive therapies Institute acute medical management Undertake invasive investigation or treatment Classify risk

In non-ACS situations Identify unsuspected Type 1 or 2 MI

Options as above After PCI or CABG

Identify Type 4 or 5 MI

To be (an MI) or not to be (an MI)?To admit or not?

Higher sensitivity TnT or TnI may Enable diagnosis of MI at lower thresholds Enable earlier triage (3 or 6h post pain)

Criteria for diagnosis of MI: Rise and/or fall but by how much?

Greater difference required at low levels of biomarker

Controversy over degree HW suggestion

Threshold change at 53ng/l (old 0.03 cut + 23 for intercept)

Levels >53 … >20% change Levels <53 … >50% change

Melanson Am J Clin Pathol 2007; 128: 282

Quicker seroconversion in NSTEMIQuicker seroconversion in NSTEMI(example using TnI Ultra)(example using TnI Ultra)

TnI-UltraTnI

51Pts with chest pain + TnT4G <0.03 →>0.03

39 (77%)1st hsTnT ≥14

12 (23%)1st hsTnT <142nd hsTnT ≥14

BUT

7 patients (14%) did not meet HW diagnostic change criteria for MI

(It has been suggested that by 6h, 95% of pats eventually diagnosable as MI will have met criteria).

Bell et al, hsTnT working group

Will we diagnose more MIs?

102 patients presenting to ED with chest pain, with Initial and 9h TnT4G values both <0.03 ng/ml hsTnT estimated, records follow-up Average follow up of 60 days (sd 12) (Incomplete review of negatives)

102Pts with chest pain +

TnT4G <0.03 X 2

30any hsTnT ≥14

72Both hsTnT <14

3*Fulfilled criteria for MI

27No MI criteria

1NSTEMIF76 6-11

To be analysed

1 (16-47)Inf STEMI @ 4d

PCI

1 (23-37)NSTEMI - PCI

3Represented with

chest pain …

1 (10-16)Represented with

chest pain

1 (13-14)+ve ETT …

*Only 3% extra diagnosable MIs on hsTnT)

Suggested hsTnT protocol for chest pain

1. Measure hsTnT on presentation.

2. If initial hsTnT ≥ 14ng/L or there is a high clinical suspicion repeat hsTnT in 3 hours, if criteria are still not met a further test at 6-9 hours may be required.

3. If initial hsTNT <14ng/L repeat hsTnT 3-6 hours after onset of symptoms.

4. If clinical suspicion remains high after 6 hours, but MI criteria are still not met, repeat hsTnT 12-24 hours after symptom onset.

What non-ACS conditions can be associated with a positive Tn?

Raised hsTnT in the “normal population”

1% (by definition) Marathon runners etc

One study – all participants had elevated TnT3G Another – 86% raised hsTnT, 45% raised TnT4G Biphasic release – early and late

Lab or labelling error Assay confounders

heterophile antibodies, scanty bodies or alkaline phosphatase interference (with troponin I)

Patients with stable CAD

Kurz et al 2008 hsTnT after stress perfusion studies

41 no defect, 41 fixed defects, 18 reversible defect No patient had significant change in hsTnT after stress

Hsieh et al (Heart and Soul Study) 2009 TnT (3rd generation) measured pre-exercise in 987 patients

with stable CAD Positive levels (>0.01 – 0.72) in 58 (6.2%)

Good indicator of future risk (58% events v 22% for –ve TnT)

Troponin T in CHF

Patients in VAL-HeFT with chronic heart failure

10.4% elevated ≥0.1ng/mL (TnT gen 4)

92% elevated ≥10ng/l (hsTnT)

Patients with elevated TnT had

more severe heart failure

older

more diabetes

more AF

higher creatinine levels Latini Circ 2007; 116: 1242

Elevations of cTn in the absence of ACSElevations of cTn in the absence of ACS- Cardiac Causes- Cardiac Causes

• Congestive heart failure • Arrhythmias, heart block• Cardiac contusion, ablation, pacing,

cardioversion, biopsy• Cardiomyopathy: HCM, Takotsubo• Inflammation - e.g. myocarditis, endocarditis• Rhabdomyolysis with cardiac injury • Infiltrative diseases, e.g., amyloidosis,

haemochromatosis, sarcoidosis, scleroderma• Drug toxicity, e.g., adriamycin, herceptin,

clozapine• Aortic dissection, aortic valve disease

• Acute and chronic renal failure• Acute neurological disease, including stroke, or

subarachnoid haemorrhage• Pulmonary embolism, severe pulmonary

hypertension• Exacerbation of CORD• Hypothyroidism• Phaeochromocytoma• Burns affecting >30% of body surface area• Critically ill patients with respiratory failure, or

sepsis• Snake bites

Elevations of cTn in the absence of ACSElevations of cTn in the absence of ACSNon-cardiac CausesNon-cardiac Causes

To be (invasive) or not to be

Interventional therapy is most beneficial in those at highest risk

Troponin level is only one of a number of measures of risk

Higher levels of troponin generally indicate higher risk

Do raised levels in the lower range predicate benefit from intervention? NB New definition requires rise and/or fall

14.5

24.2

16.914.3

0

5

10

15

20

25

30

TnT - TnT +

(%

)

CONS INV

TnT cut point = 0.01 ng/ml (54% of Pts TnT +)

OR=0.52OR=0.52(0.38,0.73)(0.38,0.73)*p<0.001*p<0.001

InteractionInteractionp<0.001p<0.001

p=NSp=NS

**

N= 414 396 463 495

Troponin T: Troponin T: 11ooEP at 6 monthsEP at 6 months

Death, MI, Rehosp ACSDeath, MI, Rehosp ACSNEJM 2001;344:1885

Subgroup analysis in TACTICS-TIMI 38

16.6

24.5

15.1 16.4

0

5

10

15

20

25

30

TnT - TnT +

(%

)

CONS INV

TnT cut point = 0.1 0.1 ng/ml (43% of Pts TnT +)

p=NSp=NS

*P<0.001*P<0.001

N= 1078 748

Troponin T: Troponin T: 11ooEP at 6 monthsEP at 6 months

Death, MI, Rehosp ACSDeath, MI, Rehosp ACSNEJM 2001;344:1884

Invasive v conservative treatment in ACS with low troponin peaks – 30 day results

Assay with +/- 10% CV at 0.05 ng/ml

Morrow et al, JAMA 2001;286(19):2405-12

4917 8 93

Events

25 14 3 61

Subgroup analysis from ICTUS

NEJM 2005;353:1095

In-trial biomarker rise threshold for diagnosing MI

Non-PCI-related PCI-related

ICTUS ULN 1.0 X ULN

FRISC II ULN 1.5 X ULN

RITA 3 ULN 2.0 X ULN

SYNERGY ULN 2.0 X ULN

TACTICS-

TIMI 18

ULN 3.0 X ULN

R

Myocardial Infarction associated Myocardial Infarction associated with PCIwith PCI

By convention, increases By convention, increases of cardiac biomarkers > 3 of cardiac biomarkers > 3 X 99th percentile are X 99th percentile are defined as PCI-related defined as PCI-related myocardial infarctionmyocardial infarction

Thygesen, Alpert, White. Universal DefinitionThygesen, Alpert, White. Universal Definition of Myocardial Infarction 2007 of Myocardial Infarction 2007 EHJ, JACC, CIRCEHJ, JACC, CIRC

Myocardial Infarction Type 4aMyocardial Infarction Type 4a

BUT: With hsTnT, this will be 3 X 14=42 ng/l (0.042 ng/ml)

So – what to do about ACS with small Tn rise?

HW – “Treat as for current NSTEMI” Does the evidence support this? The most benefit will be seen in the patients

at higher risk Troponin is one component of this risk

calculation Current ACS risk calculators are somewhat

crude

Alternative risk score – TIMI?

Age ≥ 65 years ≥ 3 Risk Factors for CAD Known CAD (stenosis ≥ 50%) ASA Use in Past 7d Severe angina (≥ 2 episodes w/in 24 hrs) ST changes ≥ 0.5mm Cardiac Biomarker +ve

(1 point for each – 0-2 low, 3-4 intermediate, 5-7 high)

Alternative risk score – GRACE?

Age (Score <40= 0 /18/36/55/73/91 =≥80) Heart rate (<70= 0/7/13/23/36/46 = ≥ 200) Systolic BP (<80= 63 /58/47/37/26/11/0 = ≥200)

Creatinine (0-35= 2 /5/8/11/14/23/31 = ≥354)

Killip Class (1= 0/21/43/64 =IV) Cardiac arrest at admission (43)

ST changes (30)

Cardiac Biomarker +ve Cardiac Biomarker +ve (15)(15)

Leader (Rothman & De Palma)Heart 30/10/09

…… it is important to remember that although much reliance has been placed on troponin release to select patients for invasive investigation, this is not the only high risk feature nor is it the main component in a patient’s assessment.

Implications of high sensitivity Implications of high sensitivity TroponinsTroponins

Increased numbers of MIs?

Earlier detection of MI earlier triage

More confusion about non-ischaemic causes

Better prognostic evaluation in ACS, heart failure, atrial fibrillation, diabetes, etc

Application of evidence-based treatment to higher risk ACS patients (RF management, ?invasive Mx)

Dealing with Troponin Elevations Dealing with Troponin Elevations in Clinical practicein Clinical practice

CP1302010-18

Changing levels are indicative of acute processes

Non changing levels are indicative of chronic processes

New syndromes are being described

If aetiology of an elevation is not clear, closely follow the patient.

Aggressively treat known pathology and risk factors eg hypertension, dyslipidaemia, diabetes etc