1. Copeptin and high sensitive Troponins Discussion of NEJM publications on sensitive Troponins BRAHMS GmbH, August 2010

2. 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

3. Simplified patient work up in the ED 3

4. 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

5. 5 Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8 Incremental value of Copeptin for rapid rule out of acute myocardial infarction

6. Combination of Copeptin / Troponin for early rule out of AMI Copeptin cut off: 14pmol/L Troponin cut off NPV (negative predictive value) = 99.4%! 6 Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8

7. Patient work up with insensitive Troponin -1 100 patientsTn < cut offTn > cut off sum non-AMI80 NSTEMI10 STEMI10 sum100 7 Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8

8. Patient work up with current Troponin -2 100 patientsTn < cut offTn > cut off sum non-AMI78280 NSTEMI10 STEMI10 sum100 8 Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8

9. 100 patientsTn < cut offTn > cut off sum non-AMI78280 NSTEMI3710 STEMI10 sum100 Patient work up with current Troponin -3 9 Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8

10. 100 patients Tn < cut off Tn > cut off sum non-AMI78280 NSTEMI3710 STEMI 10 sum8119100 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 AMI78 Tn re-test >cut off  NSTEMI3 Summary: 81 need to be re-tested!! after re-testing: 22 diagnosed with AMI, 2 false positives Patient work up with insensitive Troponin -4 10 Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8

11. 11 100 patients Tn < cut off, Copeptin < cut off Tn cut off Tn > cut off sum non-AMI280 NSTEMI710 STEMI 10 sum19100 Patient work up combining Troponin and Copeptin -1 Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8

12. 12 100 patients Tn < cut off, Copeptin < cut off Tn cut off Tn > cut off sum non-AMI6018280 NSTEMI03710 STEMI 10 sum602119100 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 AMI18 Tn re-test >cut off  NSTEMI3 Copeptin in combination with Troponin reduces re-testing by 2/3: 60 immediately ruled out, accordingly time-to-intervention reduced At the core: % NSTEMI  Tn works on AMI  Copeptin on non-AMI Patient work up combining Troponin and Copeptin -2 Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8

13. 13 100 patientsTroponin Troponin + Copeptin Troponin re-tests8121 Copeptin tests0100 non-AMI declared AMI (false positives) 22 Temporary admittance (6h) for re-testing 8121 missed AMI (false negatives ) 00 Comparing work-up of Copeptin + Troponin with Troponin alone

14. 14 Combining Troponin and Copeptin has potential to reduce costs significantly Break even point: temporary admittance = Copeptin 100 patientsTroponin Troponin + Copeptin Assumed costs per patient Troponin re-tests8121$ 20 Copeptin tests0100$ 20 Non-AMI declared AMI (false positives) 22$ 1000 Temporary admittance (6h) for re-testing 8121$ 100 Missed AMI (false negatives ) 00$ 2000 Potential savings per patient: --$ 53 Costs are based on assumptions and serve as an example only

15. 15 What sensitive Troponin assays can do Which cut off to use? 99 th percentile:  95% sensitivity,  80% specificity 99th percentile Source: Reichlin et al. J Am Coll Cardiol 2009;54:60-8

16. 16 100 patients Tn < cut off Tn > cut off sum non-AMI641680 NSTEMI1910 STEMI 10 sum6535100 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 AMI64 Tn re-test >cut off  NSTEMI1 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. 17 100 patients Tn < cut off Tn > cut off sum non-AMI641680 NSTEMI1910 STEMI 10 sum6535100 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-AMI78280 NSTEMI3710 STEMI 10 sum8119100 Patient work up with insensitive Troponin (see slide 10) Comparison between sensitive Troponin and insensitive Troponin

18. 18 99 th percentile Quite similar: 99 th percentile  88% sensitivity,  92% specificity What can sensitive Troponin do? Source: Keller et al., NEJM 36;9, 2009

19. 19 100 patients Tn < cut off Tn > cut off sum non-AMI74680 NSTEMI1910 STEMI 10 sum7525100 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 AMI74 Tn re-test >cut off  NSTEMI1 Patient work up with sensitive Troponin Change over insensitive Tn:  See next slide Source: Keller et al., NEJM 36;9, 2009

20. 100 patients Tn < cut off Tn > cut off sum non-AMI74680 NSTEMI1910 STEMI 10 sum7525100 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-AMI78280 NSTEMI3710 STEMI 10 sum8119100 Patient work up with insensitive Troponin (see slide 10) Comparison between sensitive Troponin and insensitive Troponin

21. 21 100 patientsInsensitive 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

22. 99 th percentile:  10% NSTEMI undetected 22 Finding the perfect cut-off for sensitive Troponin Best specificity at high sensitivity Best sensitivity at high specificity 99 th 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. 23 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 99 th 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. 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. 25 t0t0 t1t1 Diagnosis (insensitive Tn) NSTEMI other NSTEMI cut off Tn pat. 1 pat. 3 pat. 4 pat. 5 Tn at baseline     The (fundamental) issue of NEJM trial results simplified 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. 26 t0t0 t1t1 Diagnosis (insensitive Tn) NSTEMI other NSTEMI cut off Tn Tn at baseline Tn sens at baseline No change The (fundamental) issue of NEJM trial results simplified simulation for insensitive vs. sensitive Tn assays cut off Tn Part I: patient profiles that remain unchanged ! NSTEMI pat. 1 pat. 4 pat. 5 pat. 2 pat. 3 other          

27. 27 t0t0 t1t1 Diagnosis (insensitive Tn) NSTEMI 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 low pat. 10 other  The (fundamental) issue of NEJM trial results simplified simulation for insensitive vs. sensitive Tn assays

28. 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. 29 t0t0 t1t1 Diagnosis (sensitive Tn) NSTEMI cut off Tn pat. 6 pat. 7 pat. 8 pat. 9 Tn sens at baseline, new diagn. The (fundamental) issue of NEJM trial results simplified 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 Results not predictable pat. 10 other  NSTEMI 

30. 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. 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. 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. 33 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.)

34. Simplified work-up – quicker diagnosis possible with Copeptin (hs)Tn STEMIgo to cath lab right away no ST elevation: do first Tn do second Tn (6h later) Tn positive & changing: go to cath lab Tn negative: no AMI (hs)Tn and Copeptin STEMIGo to cath lab right away no ST elevation: do Tn and Copeptin Tn or Copeptin positive: do second Tn (6h later) Tn positive & changing: go to cath lab Tn negative: no AMI Tn and Copeptin negative: rule out AMI ~5% ~15% ~80% ~5% ~15% ~20-40% ~40-60% Need to wait for 2 nd Tn 2 nd Tn