impact of high sensitivity troponins for 6nov cardiac forum
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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
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