how will new high sensitive troponins affect the...

How will new high sensitive troponins

affect the criteria?

Hugo A Katus MDAbteilung Innere Medizin III

Kardiologie, Angiologie, Pulmologie

Universitätsklinikum Heidelberg

hsTnT (5th Generation)

99th percentile = 0.013 µg/L

Even more sensitive:

The new Troponin T assay hs

Giannitsis et al Clin Chem 2010

Criteria of Myocardial Infarction

Myocardial necrosis:

Detection of rise and/or fall of cardiac biomarker

(preferably troponins) with at least one value

above the 99th percentile of the upper reference limit

With evidence of myocardial ischemia with

at least one of the following:

• Symptoms of ischemia

• New ST-T changes or LBBB

• Development of new Q-waves

• Imaging evidence of new loss of viable myocardium

• or new regional wall motion abnormality

Universal Definition of Myocardial Infarction

The Joint ESC-ACCF-AHA-WHF Task Force

Sub-Classification of AMI

Type 1 Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as plaque erosion or rupture, fissuring or dissection

Type 2 Myocardial infarction secondary to ischemia due to imbalance between

oxygen demand and supply e.g. coronary spasm, anemia, or hypotension

Type 3 Sudden cardiac death with symptoms of ischemia, accompanied by new

ST elevation or LBBB, or verified coronary thrombus by angiography or autopsy, but death occurring before blood samples could be obtained

Type 4a Myocardial infarction associated with PCI

Type 4b Myocardial infarction associated with verified stent thrombosis

Type 5 Myocardial infarction associated with CABG

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

WHO cTnT

10%CV

cTnT

99th

hsTnT

99th

NSTEMI

UA

STEMI

216

130 165 201

181 145

64 64 64

259

87

64

Applying the Universal Definition of MI:

What Has Happened with the Diagnosis of Unstable

Angina?

unpublished

Sens

%

Spec

%

PPV NPV

Baseline sample >99th

FU sample 3hours >99th

FU sample >99th + 20%delta

FU sample >99th + 117%delta

62

100

85

69

77

77

57

100

69

65

79

100

71

100

67

88

Diagnostic performance of serial blood sampling

using 99th percentile in evolving MI

Giannitsis E, et al. Clin Chem 2010

Higher delta improves specificity

N=1530 HR 95%CI p-value

TnThs ≥14 pg/ml 7.591 1.006-57.3 0.049

Age ≥ 75 years 2.753 1.448-5.233 0.002

GFR <60 ml/min/1.73m2 2.318 1.364-3.938 0.002

TIMI Risk Score by

Tertiles1.193 0.876-1.626 0.263

NT-proBNP > 2399

pg/ml (ROC-optimized)5.698 3.252-9.983 <0.001

cTnT ≥ 0.03 µg/l 1.752 0.778-3.947 0.176

Predictors of Death at 3 years FU

Unstable angina and treatment options


Type 1 Spontaneous myocardial infarction related to ischemia due to a primary

coronary event such as plaque erosion or rupture, fissuring or dissection

Type 2 Myocardial infarction secondary to ischemia due to imbalance between oxygen demand and supply e.g. coronary spasm, anemia, or hypotension






20% of consecutive pts admitted to CPU TnThs positive !!

69% elevations are not due to clinical ACS !!

STEMI

62 pts

(1.8%)

NSTEMI

149 pts

(4.3%)

UA

173 pts

(4.9%)

TnThs positive

non-ACS

471 pts

(13.5%)

TnThs negative

non-ACS

2645 pts

(75.6%)

Median number of TnThs measurements 3 (IQR 3-5, range 2-6)

CPU Registry Heidelberg (n=3,327)

8.6.2009 – 30.11.2009 (6-months)

Diagnoses in Chest Pain Patients

High Sensitive Troponin T is a Strong Predictor of

Outcomes in Patients with Chronic Heart Failure - A

Study from the Val-HeFT Trial

Roberto Latini Heart Failure: Predicting Clinical Outcomes - Monday, November 14, 2005,

Lankeit M,….Giannitsis E, Katus HA, Konstantinides SDGK 2009; Poster

Acute Pulmonary Embolism

Probability of Long-Term Survival

hsTnT and Plaque Morphology in Stable

Coronary Artery Disease

0

10

20

30

40

50

Card

iac C

TM

-hsT

nT

(p

g/m

l)

a. d.b. c.

Normal CA Calcified CA-Pl Non Calcified CA-Pl Complex CA-Pl

Januzzi et al, 2009, Submitted

<.001

.05

.04

.001

.04

.09

.001

1.5 (±3.0)

0.8 (±2.0)

0.5 (±1.4)

1.7 (±3.0)

0.06 (±0.3)

0.05 (±0.3)

0.9 (±1.3)

4.4 (±4.0)

1.8 (±3.0)

1.4 (±2.5)

4.8 (±5.0)

0.4 (±1.0)

0.2 (±0.5)

2 (±1.8)

Coronary CT angiographySegments with calcified plaque

Segments with non-calcified plaque

Segments with mixed plaque

Segments with plaque

Segments with significant stenosis

Vessels with significant stenosis

Vessels with plaque

.02

.01

.50

.20

.01

.30

.008

95 (±24.0)

55 (17.0)

117 (±30.0)

38 (±16.0)

147 (±39.0)

68 (±9.0)

24 (8%)

107 (±33.0)

69 (±31.0)

122 (±45.0)

48 (±41.0)

173 (±60.0)

65 (±14.0)

8 (22%)

Cardiac chamber size and functionLeft atrial diastolic volume, mL

Left atrial systolic volume, mL

Left ventricular end diastolic volume, mL

Left ventricular end systolic volume, mL

Left ventricular mass

Left ventricular ejection fraction, %

Regional left ventricular dysfunction

<.001

.05

42 (23-86)

0.82 (0.73-0.92)

248 (92-492)

0.93 (0.75-1.07)

Biomarkers besides TnTNT-proBNP, pg/mL, median (interquartile range)

Cystatin-C, mg/L, median (interquartile range)

PhsTnT <13 pg/mL

(N=302)

hsTnT ≥13 pg/mL

(N=38)

Characteristic

CT angiography and biomarkers in subjects

without ACS as a function of hsTnT

1,949 patients from the Mayo Clinic registry

All had normal CK-MB after the procedure

383 (19.6%) patients with elevated cTnT

Prasad, A. et al. J Am Coll Cardiol 2006;48:1765-1770

Kaplan-Meier survival estimates for those with (TnT >=0.03) and without (TnT)

Cutoff concentrations for diagnosis of

periprocedural MI

0

10

20

30

40

50

60

70

80

90

100

3xURL

10%CV

=0.03 ng/ml

3xURL

99th perc

4th gen cTnT

=0.01 ng/ml

3xURL

99th perc

hsTnT

=14 ng/L

hsT

nT

ng

/L

0.09

ng/ml

0.03

ng/ml 42

ng/L

Elevation of troponin after

scheduled PCI: 28.7%

PCI-related MI by

Universal definition: 14.5%.

Type IV MI: Death OR 17.25 (2.71–109.96), P = 0.003,

Re-PCI OR 10.86 (3.2–36.94), P<0.001 Testa L et al. QJM 2009;102:369-378

2359 patients, 4 studies

Incidence and prognostic role of Universal Definition

Type IV MIMeta-analysis 15 studies, 7578 patients

≥3x99th percentile

<3x99th percentile

Type 4 MIs after Elective PCI

(> 3x 99th percentile = 42 pg/ml)

160

140

120

100

80

60

40

20

0

TnTbaseline Peak within 24hrs

Median 6.13

IQR2.99 to 11.31

Median 15,8

IQR 9.8 to 23.9

P = 0.0012

N=20 paired samples

Incidence Type IV MI: 10%

>3x99th percentile

Prognostic significance of preprocedural cardiac troponin

elevation among patients

with stable CAD undergoing PCI: The EVENT Registry

7592 consecutive patients

142 (6.0%) cTnT + at baselineJeremias A, et al.Circulation 2008

follow-up [days]

0 200 400 600 800 1000 1200

cu

mu

lati

ve c

ard

iac s

urv

ival [%

]

0

80

85

90

95

100

cTnT > 0,46µg/L at 48 hrs

cTnT > 0,46µg/L at 48 hrs

log rank 8.46 p = 0.0036

CTnT and Out-Come Following CABG-

Surgery

0

20

40

60

80

100

120

140

160

1 2 3

5xURL

10%CV

=0.03 ng/ml

5xURL

99th perc

4th gen cTnT

=0.01 ng/ml

5xURL

99th perc

hsTnT

=14 ng/L

hsT

nT

ng

/L

0.15

ng/ml

0.05

ng/ml70

ng/L

Cutoff concentrations for diagnosis of

MI post CABG

Mohammed, A. A. et al. Circulation 2009;120:843-850

Magnitude of cTnT release after CABG postoperative complications

Universal MI definition:

Type V MI (Periprocedural MI)

If cTn >5x99th percentile

= 0.07 ng/mL

847 consecutive patients

2% new Q-waves or LBBB

98.9% had a cTnT 0.03 ng/mL,

97.5% had a cTnT 0.10 ng/mL

Impact of hsTn on AMI Diagnosis/ Criteria

• Type 1: Many more patients rule in for AMI, prevalence of unstable angina will diminish but risk prediction will be improved

• Type 2 AMIs will remain a diagnostic challenge

• Type 4 AMI will be observed in 10-40% of elective PCIs. The prognostic impact of minor marker increases needs to be tested prospectively

• Type 5 AMI will need revision due to extra-ordinarily high rate of peri-operative AMI diagnoses and lack of prognostic information at low levels

Troponin Release: Type of Surgery

miscellaneous

CABG

Valve repair

CABG + valve

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

4 8 24 48 72 96

time after surgery

Ca

rdia

c T

rop

on

in T

(µ

g/L

)

hours

p=0.024

p=0.007

p=0.009

Short- and long-term biological

variation in hscTnT

8757.5Mean Delta Decrease, %

103.458Mean Delta Increase, %

31584.6RCV, lognormal increase, %

19.684.5Index of Individuality

9485.9CVG, %

9448.2CVI, %

Biological variation

9853.5CVA, % *

Analytical variation

Long-term

(0-8 weeks)

Short-term

(0-4 h)

Variable

0 20 40 60 80 100

100

80

60

40

20

0

100-Specificity

Se

nsitiv

ity

Sensitivity: 75,0 Specificity: 96,0 Criterion : >117,6546

Sensitivity: 78,6 Specificity: 100,0 Criterion : >242,6287

ROC 0.94

95% CI: 0.812 to 0.990

PPV 100 %

NPV 88.9 %

ROC 0.817

95% CI: 0.655 to 0.924

PPV 91.6 %

NPV 86.8 %

Optimal delta change for prediction

of evolving NSTEMI*

Giannitsis et al. Clin Chem 2010*MI defined by 4th gen. cTnT

AUC 0.885

SE 0,0157

Cutoff >112.4

P<0.0001

Maximal hsTnT within 6 hours

for prediction of MI

0 20 40 60 80 100

100

80

60

40

20

0

100-Specificity

Sensitiv

ity

Sensitivity: 77,0

Specificity: 88,2

Criterion : >112,4

Sens 77.03 (70.7 - 82.6 )

Spec 88.16 (85.2 - 90.7 )

NPV 91.3 (88.6 - 93.5 )

PPV 70.5 (64.2 - 76.4 )

100000

10000

1000

100

10

1

0,1

0,01

deltam

ax_m

inhsT

nT

ACS

N=379

non-ACS

N=395

17.3%

IQR 8.6-32.6

P<0.001

39%

IQR 14.4-139.6

Early delta change in ACS versus

TnThs-positive non-ACS patients

Diagnostic sensitivity of TnT hs

compared to cTnT

p between cTnT adm and hsTnT adm (UAP/NSTEMI) < 0.0001

p between cTnT final and hsTnT final (UAP/NSTEMI) < 0.0001

p between cTnT adm and cTnT final (UAP/NSTEMI) = 0.0003

p between hsTnT adm and hsTnT final (UAP/NSTEMI) = 0.0008

0

20

40

60

80

100

120

cTnT adm hsTnT adm cTnT final hsTnT final

STEMI

NSTEMI

UAP

non cardiac

n = 115

nu

mb

er

n

17 17 17 17

21 2121

21

20

57

32

45

31

46

22

55

Morrow, D. A. et al. Circulation 2009;119:2758-2764

Distribution of new or recurrent MIs (n=1218) by the universal definition of MI clinical

classification

0,00 200,00 400,00 600,00 800,00 1000,00 1200,00

0,4

0,5

0,6

0,7

0,8

0,9

1,0

l

All-cause Death by TnThs 99th percentile

Log rank 33.07

P<0.0001

days

Su

rviv

al

N=376

N=1154

N=1530

All-cause mortality at 3yrs follow up

cTnThs tertiles by diagnosis

N=1530

0

5

10

15

20

25

Non-STE-ACS STEMI Non-ACS

0%

5.7%

11.9%

18.9%

23.8%

2.9%0.7%

9.7%

13.5%

0/56 6/106 17/142 1/34 3/21 5/2137/3833/420 47/347

Tertile1

Median 10.9 (7.3-15.8)

Tertile2

Median 76.1 (50.5-116.5)

Tertile3

Median 524 (300.7 - 1203.8)

Latini R. et al. Circulation 2007;116

HsTnT and Outcomes in Heart Failure: The Valheft-Trial

Case 4: A 78 year old female

History:

• referred to our chest pain unit with dizziness, vomiting and nausea

• no typical cardiac chest pain

• discrete shortness of breath and decrease of performance

• known diseases: subtle renal failure (MDRD 50 ml/min/1.73m2)

• CVRF: hypertension, hypercholesterolemia

• medication: ASS 100mg 0-1-0, candesartan 16mg 1-0-1, hydrochlorothiazid

12,5mg 1-0-1, nebivolol 5mg ½-0-½, pravastatin 20mg 0-0-1, estrogen

0,6mg 1-0-0

Physical examination:

• 67.0 kg, 1.70 cm, BMI 23 kg/m2,

• RR adm 130/60mmHg, HR adm 80/min, 36.1 °C

• Auscultation: Cor/Pulmo: unsuspicious

Case 4: EKG

Case 4: Laboratory Results

admission after 24h (norm)

• creatinine 1.75 1.44 (1.1-1.3) mg/dl

• urea 100 80 (-45) mg/dl

• glucose 158 111 (70-110) mg/dl

• Hb 11.0 10.2 (12-15) g/dl

• platelets 233 231 (150-440) /nl

• white blood cells 9.34 7.82 (4-10) /nl

• C-reactive protein 9.9 8.7 (-5) mg/dl

• cTnT 0.02 0.04 0.02 (-0,03) µg/l

• hsTnT 40 60 50 30 (-14) pg/ml

• CK 44 70 (-170) U/l

• NTproBNP na (-450) ng/l

• normal values for sodium, potassium, GOT, GPT, LDH

Case 4: Left Ventricular Angiography

Case 4: Coronary Angiography

Mohammed, A. A. et al. Circulation 2009;120:843-850

Postoperative cTnT results as a function of outcome after CABG

how will new high sensitive troponins affect the...

Documents