Copeptin and high sensitive
Troponins
Discussion of NEJM publications on sensitive
Troponins
BRAHMS GmbH, August 2010
Outline
• 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)
2
Simplified patient work up in the ED
3
Only a small proportion of chest pain patients are diagnosed
with AMI
STEMI 10%
NSTEMI 10%
Source: crude average from Reichlin et al./ Keller et al., NEJM 2009
4
Incremental value of Copeptin for rapid rule out of acute
myocardial infarction
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
5
Combination of Copeptin / Troponin for early rule out of AMI
Copeptin cut off: 14pmol/L
Troponin cut off
NPV (negative predictive value) = 99.4%!
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
6
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
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
7
Patient work up with current Troponin -2
100 patients
non-AMI
Tn < cut off Tn > cut off
78
2
sum
80
NSTEMI
10
STEMI
10
sum
100
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
8
Patient work up with current Troponin -3
100 patients
Tn < cut off Tn > cut off
sum
non-AMI
78
2
80
NSTEMI
3
7
10
STEMI
sum
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
10
100
9
Patient work up with insensitive Troponin -4
100
patients
Tn <
cut off
Tn >
cut off
sum
non-AMI
78
2
80
NSTEMI
3
7
10
10
10
19
100
STEMI
sum
81
Summary:
• 81 need to be re-tested!!
• after re-testing: 22 diagnosed with
AMI, 2 false positives
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
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
10
Patient work up combining Troponin and Copeptin -1
100
patients
Tn < cut off,
Copeptin <
cut off
Tn >
cut off
sum
non-AMI
2
80
NSTEMI
7
10
STEMI
10
10
sum
19
100
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
Tn < cut off,
Copeptin >
cut off
11
Patient work up combining Troponin and Copeptin -2
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
10
10
19
100
STEMI
sum
60
21
At the core: % NSTEMI
 Tn works on AMI
 Copeptin on non-AMI
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
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
Copeptin in combination with Troponin
reduces re-testing by 2/3:
• 60 immediately ruled out, accordingly
time-to-intervention reduced
12
Comparing work-up of Copeptin + Troponin with Troponin alone
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
13
Combining Troponin and Copeptin has potential to reduce
costs significantly
Costs are based on assumptions and serve as an example only
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
Break even point: temporary admittance = Copeptin
14
What sensitive Troponin assays can do
99th percentile
Which cut off to use?
99th percentile:
 95% sensitivity,
 80% specificity
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
15
Patient work up with sensitive Troponin
100
patients
Tn <
cut off
Tn >
cut off
sum
non-AMI
64
16
80
NSTEMI
1
9
10
10
10
35
100
STEMI
sum
65
Change over insensitive Tn:
 See next slide
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
Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8
16
Comparison between sensitive Troponin and insensitive
Troponin
Patient work up with sensitive Troponin
(see slide 16)
Patient work up with insensitive Troponin
(see slide 10)
100
patients
Tn <
cut off
Tn >
cut off
sum
100
patients
Tn <
cut off
Tn >
cut off
sum
non-AMI
64
16
80
non-AMI
78
2
80
NSTEMI
1
9
10
NSTEMI
3
7
10
10
10
STEMI
10
10
35
100
sum
19
100
STEMI
sum
65
81
Change over insensitive Tn:
• 16 re-tests less: 81 - 65
• 2 NSTEMI identified earlier : 9 - 7
• 14 additional false positives!! 16 - 2
17
What can sensitive Troponin do?
99th percentile
Quite similar:
99th percentile
 88% sensitivity,
 92% specificity
Source: Keller et al., NEJM 36;9, 2009
18
Patient work up with sensitive Troponin
100
patients
Tn <
cut off
Tn >
cut off
sum
non-AMI
74
6
80
NSTEMI
1
9
10
10
10
25
100
STEMI
sum
75
Change over insensitive Tn:
 See next slide
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
Source: Keller et al., NEJM 36;9, 2009
19
Comparison between sensitive Troponin and insensitive
Troponin
Patient work up with sensitive Troponin
(see slide 19)
Patient work up with insensitive Troponin
(see slide 10)
100
patients
Tn <
cut off
Tn >
cut off
sum
100
patients
Tn <
cut off
Tn >
cut off
sum
non-AMI
74
6
80
non-AMI
78
2
80
NSTEMI
1
9
10
NSTEMI
3
7
10
10
10
STEMI
10
10
25
100
sum
19
100
STEMI
sum
75
81
Change over insensitive Tn:
• 6 re-tests less: 81 - 75
• 2 NSTEMI identified earlier : 9 - 7
• 4 additional false positives!! 6 - 2
20
Combining Troponin and Copeptin has potential to reduce
costs significantly
100 patients
Insensitive
Troponin
Sensitive
Troponin
Insensitive
Troponin +
Copeptin
Sensitive
Troponin +
Copeptin
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:
21
assumed
costs p.p.
Finding the perfect cut-off for sensitive Troponin
99th percentile:
 10% NSTEMI undetected
Best sensitivity at high specificity
 20% NSTEMI undetected
Best specificity at
high sensitivity
99th percentile
Best sensitivity at
high specificity
Best specificity at high sensitivity
 4 out of 5 tests positives are
false positives!
Yet another issue...
22
NSTEMI: Troponin plays a key role in AMI definition
New Definition of AMI (since 2000)
Criteria for acute Myocardial Infarction
I. 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
23
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
24
The (fundamental) issue of NEJM trial results
simplified simulation for insensitive Tn assays
t0
Diagnosis
(insensitive Tn)
Tn at
baseline
pat. 1
NSTEMI

pat. 2
other
pat. 3
NSTEMI


pat. 4
NSTEMI

pat. 5
other

t1
cut off Tn
Results of Gold Standard
Diagnosis using
insensitive Tn assays
Comparing insensitive
Tn at baseline with
Gold Standard
Diagnosis
25
The (fundamental) issue of NEJM trial results
simplified simulation for insensitive vs. sensitive Tn assays
t0
Diagnosis
(insensitive Tn)
Tn at
baseline
Tn sens at
baseline
pat. 1
NSTEMI


pat. 2
other
pat. 3
NSTEMI




pat. 4
NSTEMI


pat. 5
other


t1
cut off Tn
cut off Tn
Part I: patient profiles that
remain unchanged !
No change
26
The (fundamental) issue of NEJM trial results
simplified simulation for insensitive vs. sensitive Tn assays
t0
cut off Tn
Diagnosis
(insensitive Tn)
Tn at
baseline
Tn sens at
baseline
pat. 6
NSTEMI


pat. 7
other
pat. 8
other
pat. 9
other






pat. 10
other


t1
cut off Tn
Part II: additional patient
profiles!
improves Tn sens
performance
worsens Tn sens
performance if cut
off is chosen too
low
No additional NSTEMI
observable that are
sensitive Tn negative
27
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?
28
The (fundamental) issue of NEJM trial results
simplified simulation for future Gold Standard Diagnosis
t0
cut off Tn
Diagnosis
Diagnosis
(insensitive Tn) (sensitive Tn)
t1
Tn sens at
baseline,
old diagn.
Tn sens at
baseline,
new diagn.
pat. 6
NSTEMI
NSTEMI


pat. 7
other
NSTEMI
pat. 8
other
other
pat. 9
other
NSTEMI






pat. 10
other
NSTEMI


cut off Tn
Part III: Gold Standard
Diagnosis using sensitive Tn
Results not predictable
29
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
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
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
31
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)
32
Conclusions
The Copeptin algorithm
A 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.)
33
Simplified work-up – quicker diagnosis possible with Copeptin
STEMI
go to cath lab right away
(hs)Tn
no ST elevation:
do first Tn
STEMI
(hs)Tn and
Copeptin
no ST elevation:
do Tn and
Copeptin
~5%
Tn positive &
changing: go to
cath lab
~15%
Tn negative:
no AMI
~80%
do second Tn
(6h later)
Go to cath lab right away
Tn or Copeptin
positive:
do second Tn
(6h later)
Tn positive &
changing: go to
cath lab
Need to
wait for
2nd Tn
~5%
~15%
2nd
Tn
Tn negative:
no AMI
~20-40%
Tn and Copeptin negative: rule out AMI
~40-60%