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

Troponin 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

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 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 Negative (Normal, and ‘analytically indistinguishable from normal’) ACS threshold (LOD with 10% CV) Equivalent to WHO definition of MI standard TnI 0.05 ug/L 0.5 ug/L 14 ng/L hs-TnT 99%ile NORMAL Myocardial infarction (MI) by new definition if clinical features exist

Troponin I vs hs-Troponin T MI if clinical features exist Negative (Normal, and ‘analytically indistinguishable from normal’) ACS threshold (LOD with 10% CV) Equivalent to WHO definition of MI standard TnI 0.05 ug/L 0.5 ug/L 14 ng/L 30 ng/L hs-TnT ACS threshold From 0.05 using TnI 99%ile NORMAL 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 8h post-pain onset Reichlin et al. NEJM (2009) 361: 858

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 100% patients (303/303) with normal or indeterminate TnT on admission had repeat at 8 hr post pain / event 93% patients (182/196) with normal TnT at 8 hr did not have a repeat test at 12 hr 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 83/303 Normal 220/303 Negative predictive value 89% On admission Indet 20/220 Positive 4/220 Normal 12/83 8h Positive 15/83 8h Indet 56/83 Normal 196/220 Positive 2/56 >12h >12h Indet 25/56 Not measured 28/56 Indet 8/20 Not measured 12/20 Normal 1/56

Time of admission after pain onset of all patients with TnT > 30 ng/L during admission TnT 26 32 (at 12h) ‘collapse’ TnT 28 30 (at 20h) SOB, COPD, pulm oedema, PPM. Multiple adm TnT 25-45 No of patients Positive on adm Indet - positive n=88 Normal - positive Time (h) after pain onset of adm TnT STEMI 1 patient-critical AS 2 patients-early presentation

Patients with indeterminate – normal or normal - indeterminate No of patients Indet - normal Normal - indet Time after pain onset of adm TnT No of patients No of patients Adm TnT (ng/L) indet – normal pts 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 > 99th 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 99th 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