High Sensitivity TroponinOne year on in the South West

Charlotte DawsonSpR Chemical Pathology / Metabolic Medicine

Bristol Royal Infirmary

2000 • 1st generation troponin assays routinely replaced cardiac

marker panels (CK, CK-MB, myoglobin) as diagnostic test for acute coronary syndrome (ACS)

• Specific for myocardial injury measured >12h after onset of chest pain– STEMI: confirms diagnosis and estimates infarct size– Normal or equivocal ECGs: distinguishes between NSTEMI and other

causes of chest pain where myocardial injury has not occurred

• Limitation was poor sensitivity in the first few hours after pain onset– Delayed treatment– Delayed discharge from A&E / hospital

Troponin

High Sensitivity Troponin (hs-Tn)

2007

• ESC-ACCF-AHA-WHF and IFCC Task Force recommends use of a high sensitivity troponin assay

• Requirements were detection of hs-Tn at the 99th percentile of an apparently healthy reference population with <10% variability

• New definition of myocardial infarction: hs-Tn >99th percentile (hs-TnT >14 ng/L) with clinical features

hs-TnT (ng/L)

99th percentile10% CV

Thygesen et al. Eur Heart J (2007) 28: 2525

Diagnosis of acute MI (AMI) after pain onset hs-Tn vs standard assay

Keller et al NEJM (2009) 361: 868-877

= hs-TnT>14 ng/L

= TnI >0.05 ug/L

Troponin I vs hs-Troponin T

standard TnI

hs-TnT

0.05 ug/L 0.5 ug/L

14 ng/L

99%ile

NORMAL Myocardial infarction (MI) by new definition if clinical features exist

Equivalent to WHO definition of MI

Negative (Normal, and ‘analytically

indistinguishable from normal’)

ACS threshold(LOD with 10% CV)

hs-TnT

0.05 ug/L 0.5 ug/L

30 ng/L14 ng/L

99%ile

ACS thresholdFrom 0.05 using TnI

NORMAL INDETERMINATE MI if clinical features exist

Equivalent to WHO definition of MI

Negative (Normal, and ‘analytically

indistinguishable from normal’)

ACS threshold(LOD with 10% CV)

Troponin I vs hs-Troponin T

standard TnI

Causes of elevated troponin in the absence of overt ischaemic heart disease

Congestive heart failure—acute and chronicPulmonary embolism, severe pulmonary hypertensionRhabdomyolysis with cardiac injuryInflammatory diseases, e.g. myocarditis Critically ill patients, especially with respiratory failure or sepsisRenal failureCardiac contusion, or other trauma including surgery, ablation, pacing, etc Aortic dissectionAortic valve diseaseHypertrophic cardiomyopathyTachy- or bradyarrhythmias, or heart blockAcute neurological disease, including stroke or subarachnoid haemorrhageDrug toxicity or toxins

Reichlin et al. NEJM (2009) 361: 858

8h post-pain onset

Timing of sampling using hs-Tn assays

Study aims

• Audit adherence to protocol

• Establish whether time of second measurement can be earlier than 8 hours

• Monitor troponin outcome of patients admitted with ‘indeterminate’ result

Adherence to Protocol- audit results

1. 100% patients (303/303) with normal or indeterminate TnT on admission had repeat at 8 hr post pain / event

2. 93% patients (182/196) with normal TnT at 8 hr did not have a repeat test at 12 hr

3. 50% patients (36/76) with indeterminate result at 8 hr had repeat test at 12 hr

Normal220/303

Indeterminate83/303

Patients with normal (<14 ng/L) or indeterminate (14-29 ng/L) TnT on adm

Normal196/220

Indet20/220

Positive4/220

Indet 56/83

Normal 12/83

Positive 15/83

Not measured28/56

Indet25/56

Normal 1/56

Positive 2/56

8h

>12h

8h

>12h

On admission

Negative predictive value 89%

Not measured12/20

Indet8/20

Time (h) after pain onset of adm TnT

TnT 26 32 (at 12h)‘collapse’

TnT 28 30 (at 20h)SOB, COPD, pulm oedema, PPM. Multiple adm TnT 25-45

Positive on adm

Indet - positive

Normal - positive

0

5

10

15

20

25

30

0-0.9 1.0-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6-6.9 7-7.9

No

of

patie

nts

Time of admission after pain onset of all patients with TnT > 30 ng/L during admission

n=88

STEMI

1 patient-critical AS2 patients-early presentation

Patients with indeterminate – normal or normal - indeterminate

Time after pain onset of adm TnT

No

of

patie

nts

0

1

2

3

4

5

6

7

8

9

10

0-0.9 1.0-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6-6.9 7-7.9 >8 Normal - indet

Indet - normal

0

1

2

3

4

5

6

7

14 15 16 17 18 19 20 21-25 26-29

Adm TnT (ng/L) indet – normal pts

No

of

patie

nts

0

1

2

3

4

5

6

14 15 16 17 18 19 20 21-25 26-29

Max TnT (ng/L) normal - indet pts

No

of

patie

nts

• Indet – normal patients are not presenting later• Normal – indet patients are not presenting earlier• Majority have indeterminate levels at the lower end of the range

? Distinctprognostic gp

Improved survival of indeterminate patients once results start being reported (validation phase vs implementation phase)

Survival of patients according to hs-Tn level

Mills et al. JAMA (2011) 305: 1210-1216

• Intra individual variation 15-21% for hs-TnT (9.7% for hs-TnI)

• Based on 10% CV at 95% probability, studies suggest increase of 90% for hs-TnT (46% for hs-TnI) is a significant increase = acute MI

• Optimal increase may be 235 – 245%

• In clinical practice recommend• rise in troponin to > 99th percentile AND• doubling of hs-TnT

Diagnosis of acute MI using hs-TnI – single vs serial measurements

Collinson PO J Clin Pathol (2011) doi:10.1136

Higher diagnostic accuracy for acute MI using absolute change of >50% of the 99th percentile value ie 7 ng/L.

1 hour 2 hoursInterval between hs-Tn measurements

Summary

• hs-Tn allows for more rapid diagnosis of MI • Optimal timing for ruling out acute MI uncertain -

4 – 6 hours after pain onset

• Identifies ‘indeterminate’ patients in a poor prognostic group and need further investigation

• Change in troponin level may be informative in identifying acute MI in this group – more work needed