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Copeptin and high sensitive Troponins
Discussion of NEJM publications on sensitive Troponins
BRAHMS GmbH, August 2010
• What Copeptin can do• Translating results into work-up changes (simplified)
• What sensitive Troponin assays can do• Translating results into work up changes (simplified)
• The issues of current trial results evaluating sensitive Troponin (New England Journal, 2009)
Outline
2
Only a small proportion of chest pain patients are diagnosed with AMI
Source: crude average from Reichlin et al./ Keller et al., NEJM 2009
STEMI 10%
NSTEMI 10%
4
5Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
Incremental value of Copeptin for rapid rule out of acute myocardial infarction
Combination of Copeptin / Troponin for early rule out of AMI
Copeptin cut off: 14pmol/L
Troponin cut off
NPV (negative predictive value) = 99.4%!
6Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
Patient work up with insensitive Troponin -1
100 patients Tn < cut off Tn > cut off sum
non-AMI 80
NSTEMI 10
STEMI 10
sum 100
7Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
Patient work up with current Troponin -2
100 patients Tn < cut off Tn > cut off sum
non-AMI 78 2 80
NSTEMI 10
STEMI 10
sum 100
8Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
100 patients Tn < cut off Tn > cut off sum
non-AMI 78 2 80
NSTEMI 3 7 10
STEMI 10
sum 100
Patient work up with current Troponin -3
9Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
100 patients
Tn < cut off
Tn > cut off
sum
non-AMI 78 2 80
NSTEMI 3 7 10
STEMI 10 10
sum 81 19 100
19 patients Tn positive: Highly suspicious for AMI, start treatment or confirmatory diagnosis 17 with AMI
81 patients Tn negative: Unclear on admission if NSTEMI to be re-tested
Tn re-test <cut off no AMI 78
Tn re-test >cut off NSTEMI 3
Summary:•81 need to be re-tested!!•after re-testing: 22 diagnosed with AMI, 2 false positives
Patient work up with insensitive Troponin -4
10Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
11
100 patients
Tn < cut off, Copeptin <
cut off
Tn < cut off, Copeptin >
cut off
Tn > cut off sum
non-AMI 2 80
NSTEMI 7 10
STEMI 10 10
sum 19 100
Patient work up combining Troponin and Copeptin -1
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
12
100 patients
Tn < cut off, Copeptin <
cut off
Tn < cut off, Copeptin >
cut off
Tn > cut off sum
non-AMI 60 18 2 80
NSTEMI 0 3 7 10
STEMI 10 10
sum 60 21 19 100
60 patients Tn & Copeptin neg.: very unlikely to have AMI NPV 99.4% rule out
21 patients Tn neg, Copeptin pos.: unclear on admission if NSTEMI to be re-tested
Tn re-test <cut off no AMI 18
Tn re-test >cut off NSTEMI 3
Copeptin in combination with Troponin reduces re-testing by 2/3:•60 immediately ruled out, accordingly time-to-intervention reduced
At the core: % NSTEMITn works on AMICopeptin on non-AMI
Patient work up combining Troponin and Copeptin -2
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
13
100 patients Troponin Troponin + Copeptin
Troponin re-tests 81 21
Copeptin tests 0 100
non-AMI declared AMI(false positives)
2 2
Temporary admittance (6h) for re-testing
81 21
missed AMI (false negatives )
0 0
Comparing work-up of Copeptin + Troponin with Troponin alone
14
Combining Troponin and Copeptin has potential to reduce costs significantly
Break even point: temporary admittance = Copeptin
100 patients Troponin Troponin + Copeptin
Assumed costs per patient
Troponin re-tests 81 21 $ 20
Copeptin tests 0 100 $ 20
Non-AMI declared AMI(false positives)
2 2 $ 1000
Temporary admittance (6h) for re-testing
81 21 $ 100
Missed AMI (false negatives )
0 0 $ 2000
Potential savings per patient:
-- $ 53
Costs are based on assumptions and serve as an example only
15
What sensitive Troponin assays can do
Which cut off to use?99th percentile: 95% sensitivity, 80% specificity
99th percentile
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
16
100 patients
Tn < cut off
Tn > cut off
sum
non-AMI 64 16 80
NSTEMI 1 9 10
STEMI 10 10
sum 65 35 100
35 patients Tn positive: highly suspicious for AMI, start treatment or confirmatory diagnosis 19 with AMI
65 patients Tn negative: unclear on admission if NSTEMI to be re-tested
Tn re-test <cut off no AMI 64
Tn re-test >cut off NSTEMI 1
Change over insensitive Tn: See next slide
Patient work up with sensitive Troponin
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
17
100 patients
Tn < cut off
Tn > cut off
sum
non-AMI 64 16 80
NSTEMI 1 9 10
STEMI 10 10
sum 65 35 100
Change over insensitive Tn:• 16 re-tests less: 81 - 65• 2 NSTEMI identified earlier : 9 - 7 • 14 additional false positives!! 16 - 2
Patient work up with sensitive Troponin(see slide 16)
100 patients
Tn < cut off
Tn > cut off
sum
non-AMI 78 2 80
NSTEMI 3 7 10
STEMI 10 10
sum 81 19 100
Patient work up with insensitive Troponin(see slide 10)
Comparison between sensitive Troponin and insensitive Troponin
18
99th percentile
Quite similar: 99th percentile 88% sensitivity, 92% specificity
What can sensitive Troponin do?
Source: Keller et al., NEJM 36;9, 2009
19
100 patients
Tn < cut off
Tn > cut off
sum
non-AMI 74 6 80
NSTEMI 1 9 10
STEMI 10 10
sum 75 25 100
25 patients Tn positive: Highly suspicious for AMI, start treatment or confirmatory diagnosis 19 with AMI
75 patients Tn negative: Unclear on admission if NSTEMI to be re-tested
Tn re-test <cut off no AMI 74
Tn re-test >cut off NSTEMI 1
Patient work up with sensitive Troponin
Change over insensitive Tn: See next slide
Source: Keller et al., NEJM 36;9, 2009
100 patients
Tn < cut off
Tn > cut off
sum
non-AMI 74 6 80
NSTEMI 1 9 10
STEMI 10 10
sum 75 25 100
20
Change over insensitive Tn:• 6 re-tests less: 81 - 75• 2 NSTEMI identified earlier : 9 - 7 • 4 additional false positives!! 6 - 2
Patient work up with sensitive Troponin(see slide 19)
100 patients
Tn < cut off
Tn > cut off
sum
non-AMI 78 2 80
NSTEMI 3 7 10
STEMI 10 10
sum 81 19 100
Patient work up with insensitive Troponin(see slide 10)
Comparison between sensitive Troponin and insensitive Troponin
21
100 patients Insensitive Troponin
Sensitive Troponin
Insensitive Troponin + Copeptin
Sensitive Troponin + Copeptin
assumed costs p.p.
Troponin re-tests
Copeptin tests
non-AMI declared AMI(false positives)
Temporary admittance (6h) for re-testing
missed AMI (false negatives )
Potential savings per patient:
Combining Troponin and Copeptin has potential to reduce costs significantly
99th percentile: 10% NSTEMI undetected
22
Finding the perfect cut-off for sensitive Troponin
Best specificity at high sensitivity
Best sensitivity at high specificity
99th percentile
Best sensitivity at high specificity 20% NSTEMI undetected
Best specificity at high sensitivity 4 out of 5 tests positives are false positives!
Yet another issue...
23
NSTEMI: Troponin plays a key role in AMI definition
New Definition of AMI (since 2000)
Criteria for acute Myocardial InfarctionI. 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 (URL) together with evidence of myocardial ischemia with at least one of the following:
- Clinical symptoms of ischemia
- ECG change indicative of new ischemia
- Imaging evidence of new loss of viable myocardium
II. Sudden, unexpected cardiac death
III. Pathological findings of an acute myocardial infarction in autopsy
Source: Thygesen et al. Universal Definition of Myocardial Infarction; J Am Coll Cardiol 2007; 50(22):2137-2195
24
The (fundamental) issue of NEJM trial results
Troponin plays a key role in NSTEMI definition; for the discussed data sets, therefore
more sensitive Tn detects less sensitive Tn
no additional NSTEMI observable that are sensitive Tn negative
25
t0 t1
Diagnosis (insensitive Tn)
NSTEMI
NSTEMI
other
NSTEMI
cut off Tn
pat. 1
pat. 3
pat. 4
pat. 5
Tn at baseline
The (fundamental) issue of NEJM trial resultssimplified simulation for insensitive Tn assays
pat. 2 other
Results of Gold Standard Diagnosis using insensitive Tn assays
Comparing insensitive Tn at baseline with Gold Standard Diagnosis
26
t0 t1
Diagnosis (insensitive Tn)
NSTEMI
other
NSTEMI
cut off Tn
Tn at baseline
Tn sens at baseline
No change
The (fundamental) issue of NEJM trial resultssimplified simulation for insensitive vs. sensitive Tn assays
cut off Tn
Part I: patient profiles that remain unchanged !
NSTEMIpat. 1
pat. 4
pat. 5
pat. 2
pat. 3
other
27
t0 t1
Diagnosis (insensitive Tn)
NSTEMI
other
other
cut off Tn
pat. 6
pat. 7
pat. 8
pat. 9
Tn at baseline
Tn sens at baseline
cut off Tn
Part II: additional patient profiles!
other
No additional NSTEMI observable that are
sensitive Tn negative
improves Tn sens performance
worsens Tn sens performance if cut off is chosen too lowpat. 10 other
The (fundamental) issue of NEJM trial resultssimplified simulation for insensitive vs. sensitive Tn assays
28
The (fundamental) issue of NEJM trial results
Troponin plays a key role in NSTEMI definition; for the discussed data sets, therefore
more sensitive Tn detects less sensitive Tn
no additional NSTEMI observable that are sensitive Tn negative
What are the consequences if sensitive Troponin is used for definition of AMI?
29
t0 t1
Diagnosis (sensitive Tn)
NSTEMI
NSTEMI
NSTEMI
cut off Tn
pat. 6
pat. 7
pat. 8
pat. 9
Tn sens at baseline,
new diagn.
The (fundamental) issue of NEJM trial resultssimplified simulation for future Gold Standard Diagnosis
cut off Tn
Part III: Gold Standard Diagnosis using sensitive Tn
other
Tn sens at baseline, old diagn.
Diagnosis (insensitive Tn)
NSTEMI
other
other
other
Results not predictable
pat. 10 other NSTEMI
30
The (fundamental) issue of NEJM trial results
Troponin plays a key role in NSTEMI definition, for current data sets, therefore more sensitive Tn detects less sensitive Tn no additional NSTEMI observable that are sensitive Tn negative
What are the consequences if sensitive Troponin is used for definition of AMI definition? applied to data set from Keller et al.*: 30% NSTEMI
* Keller et al. Copeptin Improves Early Diagnosis of Acute Myocardial Infarction; J Am Coll Cardiol 2010; 55(19): 2096-106
31
The (fundamental) issue of NEJM trial results
Troponin plays a key role in NSTEMI definition, for current data sets, therefore more sensitive Tn detects less sensitive Tn no additional NSTEMI observable that are sensitive Tn negative
What are the consequences if sensitive Troponin is used for definition of AMI definition? applied to data set from Keller et al.*: 30% NSTEMI
Advantage Copeptin: Copeptin is unrelated to Tn/AMI definition different pathological pathway very low risk that results are biased ROC curves may look similar, but information is not
32
Summary
The Copeptin algorithm
A useful and easy-to-use algorithm in chest pain:
negative Troponin as AMI rule out (insensitive or sensitive Tn)
together with a
negative Copeptin as AMI rule out (reason: low number of AMI)
33
Conclusions
The Copeptin algorithmA useful (but simplified) algorithm in chest pain:
• high Troponin as AMI rule in (current or sensitive Tn)• low Copeptin as AMI rule out
Reason: low number of AMI
Sensitive Troponin results are not easy to interpret• first value still needs to be verified by serial measurement after 6 hours• sensitive Troponin causes false positive values• many areas where sensitive Troponin is not available (general
practitioner, hospitals without high throughput labs etc.)