High Sensitivity Troponin

One year on in the South West Charlotte Dawson SpR Chemical Pathology / Metabolic Medicine Bristol Royal Infirmary

Troponin

2000

• 1 st 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

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 >99 th percentile (hs-TnT >14 ng/L) with clinical features

hs-TnT (ng/L)

99 th percentile 10% CV Thygesen et al. Eur Heart J (2007) 28: 2525

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

= hs-TnT>14 ng/L = TnI >0.05 ug/L Keller et al NEJM (2009) 361: 868-877

Troponin I vs hs-Troponin T

standard TnI

Negative (Normal, and ‘analytically indistinguishable from normal’) ACS threshold (LOD with 10% CV) Equivalent to WHO definition of MI 0.05 ug/L 0.5 ug/L 14 ng/L

hs-TnT NORMAL

99%ile

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

Troponin I vs hs-Troponin T

standard TnI

Negative (Normal, and ‘analytically indistinguishable from normal’) ACS threshold (LOD with 10% CV) Equivalent to WHO definition of MI 14 ng/L 0.05 ug/L 30 ng/L 0.5 ug/L

hs-TnT NORMAL

99%ile ACS threshold From 0.05 using TnI

INDETERMINATE MI if clinical features exist

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

Congestive heart failure —acute and chronic Pulmonary embolism, severe pulmonary hypertension Rhabdomyolysis with cardiac injury Inflammatory diseases, e.g. myocarditis Critically ill patients, especially with respiratory failure or sepsis Renal failure Cardiac contusion, or other trauma including surgery, ablation, pacing, etc Aortic dissection Aortic valve disease Hypertrophic cardiomyopathy Tachy- or bradyarrhythmias, or heart block Acute neurological disease, including stroke or subarachnoid haemorrhage Drug toxicity or toxins

Timing of sampling using hs-Tn assays

Reichlin et al. NEJM (2009) 361: 858 8h post-pain onset

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

Patients with normal (<14 ng/L) or indeterminate (14-29 ng/L) TnT on adm Indeterminate 83/303 Normal 220/303 Positive 15/83 Normal 12/83 8h Indet 56/83 Indet 25/56 Positive 2/56 >12h Not measured 28/56 Normal 1/56 On admission Indet 20/220 Negative predictive value 89% Positive 4/220 8h Normal 196/220 Indet 8/20 >12h Not measured 12/20

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

30 25 20 15 10 TnT 26 32 (at 12h) ‘collapse’ TnT 28 30 (at 20h) SOB, COPD, pulm oedema, PPM. Multiple adm TnT 25-45 5 0 n=88 0-0.9 1.0-1.9

2-2.9

3-3.9

4-4.9

5-5.9

6-6.9

Time (h) after pain onset of adm TnT STEMI 1 patient-critical AS 2 patients-early presentation 7-7.9

Positive on adm Indet - positive Normal - positive

Patients with indeterminate – normal or normal - indeterminate

5 4 3 2 1 0 10 9 8 7 6 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

Time after pain onset of adm TnT >8 Indet - normal Normal - indet 3 2 1 0 7 6 5 4 14 15 16 17 18 19 20 21-25 26-29

Adm TnT (ng/L) indet – normal pts

6 5 1 0 4 3 2 14 15 16 17 18 19 20 21-25 26-29

Max TnT (ng/L) normal - indet pts

• 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

? Distinct prognostic gp

Survival of patients according to hs-Tn level

Improved survival of indeterminate patients once results start being reported (validation phase vs implementation phase) Mills et al. JAMA (2011) 305: 1210-1216

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

• 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 > 99 th percentile AND • doubling of hs-TnT Collinson PO J Clin Pathol (2011) doi:10.1136

Interval between hs-Tn measurements

1 hour 2 hours Higher diagnostic accuracy for acute MI using absolute change of >50% of the 99 th percentile value ie 7 ng/L.

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