Impact of highsensitivity Troponins (T and I)

Stewart Mann
UoW/CCDHB

Cardiac 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 Myocardial Infarction

The ESC-ACC-AHA-WHF Criteria
Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit together with evidence of ischemia with at least one of the following

Symptoms of ischemia
ECG changes of new ischemia (new ST-T changes or new LBBB) Development of pathologic Q waves Imaging evidence of new loss of viable myocardium or new regional
wall motion abnormality
Thygesen, Alpert, White. Universal Definition of Myocardial Infarction 2007 EHJ, JACC, CIRC

Clinical Classification of different Types of Myocardial Infarction

Type 1 Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as plaque erosion or rupture Myocardial infarction secondary to ischemia due to imbalance between oxygen demand and supply e.g. coronary spasm 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 2

Type 3

Type 4a Myocardial infarction associated with PCI Type 4b Myocardial infarction associated with stent thrombosis Type 5 Myocardial infarction associated with CABG
Thygesen, Alpert, White. Universal Definition of Myocardial Infarction 2007 EHJ, JACC, CIRC

NACB and IFCC Guidelines for cardiac biomarkers

Reference decision-limits should be established for each cardiac biomarker on a population of normal, healthy individuals without a known history of heart disease (reference population) For cardiac troponin an increased value should be defined as a measurement exceeding the 99th percentile of a reference control group Acceptable imprecision at the 99th percentile for each 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 LoD Analytical sens 0.01 ng/ml 0.01 - 25 ng/ml < 0.01 ng/ml 0.003 ng/ml

TnT-hs

range 99th percentile

0.003 -10 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 g/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 but intercept up to 23 ng/l (higher for hsTnT) Will replace current 4th generation test No additional cost

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

Jarausch Clinc Chem 2008; 54: B133

WRH Lab comparison of hsTnT to 4th generation TnT

120 hs-TNT

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

100

80

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

60

r=0.975
40

n=41

20

0 0

TNT 20 40 60 80 Passing-Bablok agreement test N = 0 Slope : 0.943 [ 0.874 to 1.008 ] Intercept : 9.762 [ 8.204 to 12.356 ] 100 120

Introduction of High Sensitivity Troponins: Implications for clinical practice

Improved diagnosis of ACS Improved risk stratification in ACS Improved risk stratification in non-ACS 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

Identify Type 4 or 5 MI

After PCI or CABG

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

Quicker seroconversion in NSTEMI (example using TnI Ultra)

TnI-Ultra TnI

Melanson Am J Clin Pathol 2007; 128: 282

51 Pts with chest pain + TnT4G <0.03 >0.03

39 (77%) 1st hsTnT 14

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

12 (23%) 1st hsTnT <14 2nd hsTnT 14

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

102 Pts with chest pain + TnT4G <0.03 X 2

30 any hsTnT 14

72 Both hsTnT <14

3* Fulfilled criteria for MI

27 No MI criteria

1 NSTEMI F76 6-11

To be analysed

1 (16-47) Inf STEMI @ 4d PCI

3 Represented with chest pain

1 (23-37) NSTEMI - PCI

1 (13-14) +ve ETT

1 (10-16) Represented with chest pain

*Only 3% extra diagnosable MIs on hsTnT)

Suggested hsTnT protocol for chest pain

1. 2.

3. 4.

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

Hsieh et al (Heart and Soul Study) 2009

(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 ACS - 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

Elevations of cTn in the absence of ACS Non-cardiac Causes

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

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

Troponin T: 1oEP at 6 months

Death, MI, Rehosp ACS
NEJM 2001;344:1885

30 25 20
(%)

CONS

INV

*
24.2

p=NS
14.5 16.9

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

Interaction p<0.001 14.3

15 10 5 0
N=

414

396

463

495

TnT TnT cut point = 0.01 ng/ml

TnT + (54% of Pts TnT +)

Subgroup analysis in TACTICS-TIMI 38

Troponin T: 1oEP at 6 months

Death, MI, Rehosp ACS
NEJM 2001;344:1884

*P<0.001
30 25 20
(%)
CONS INV

p=NS
16.6 15.1

24.5 16.4

15 10 5 0
N= 1078 748

TnT TnT cut point = 0.1 ng/ml

TnT + (43% of Pts TnT +)

Invasive v conservative treatment in ACS with low troponin peaks 30 day results
Assay with +/- 10% CV at 0.05 ng/ml

Events 49 17 8 93

25 14 3 61

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

Subgroup analysis from ICTUS

NEJM 2005;353:1095

In-trial biomarker rise threshold for diagnosing MI

Non-PCI-related ICTUS FRISC II RITA 3 SYNERGY TACTICSTIMI 18 ULN ULN ULN ULN ULN PCI-related 1.0 X ULN 1.5 X ULN 2.0 X ULN 2.0 X ULN 3.0 X ULN

Myocardial Infarction associated with PCI

Myocardial Infarction Type 4a
By convention, increases of cardiac biomarkers > 3 X 99th percentile are defined as PCI-related myocardial infarction
Thygesen, Alpert, White. Universal Definition of Myocardial Infarction 2007 EHJ, JACC, CIRC

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

R

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 (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 patients assessment.

Implications of high sensitivity Troponins

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 in Clinical practice

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

CP1302010-18