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Copeptin and high sensitive Troponins

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

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Copeptin and high sensitive Troponins

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

  2. 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)

  3. Simplified patient work up in the ED

  4. 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

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

  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%! Source: Reichlin et al. J Am CollCardiol 2009;54:60-8

  7. Patient work up with insensitive Troponin -1 Source: Reichlin et al. J Am CollCardiol 2009;54:60-8

  8. Patient work up with current Troponin -2 Source: Reichlin et al. J Am CollCardiol 2009;54:60-8

  9. Patient work up with current Troponin -3 Source: Reichlin et al. J Am CollCardiol 2009;54:60-8

  10. Patient work up with insensitive Troponin -4 • 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 Source: Reichlin et al. J Am CollCardiol 2009;54:60-8

  11. Patient work up combining Troponin and Copeptin -1 Source: Reichlin et al. J Am CollCardiol 2009;54:60-8

  12. Patient work up combining Troponin and Copeptin -2 • 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 • Copeptin in combination with Troponin reduces re-testing by 2/3: • 60 immediately ruled out, accordingly time-to-intervention reduced 21 patients Tn neg, Copeptin pos.: unclear on admission if NSTEMI  to be re-tested Source: Reichlin et al. J Am CollCardiol 2009;54:60-8

  13. Comparing work-up of Copeptin + Troponin with Troponin alone

  14. Combining Troponin and Copeptin has potential to reduce costs significantly Costs are based on assumptions and serve as an example only Break even point: temporary admittance = Copeptin

  15. 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 CollCardiol 2009;54:60-8

  16. Patient work up with sensitive Troponin 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 Source: Reichlin et al. J Am CollCardiol 2009;54:60-8

  17. 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) • Change over insensitive Tn: • 16 re-tests less: 81 - 65 • 2 NSTEMI identified earlier : 9 - 7 • 14 additional false positives!! 16 - 2

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

  19. Patient work up with sensitive Troponin 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 Source: Keller et al., NEJM 36;9, 2009

  20. 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) • Change over insensitive Tn: • 6 re-tests less: 81 - 75 • 2 NSTEMI identified earlier : 9 - 7 • 4 additional false positives!! 6 - 2

  21. Combining Troponin and Copeptin has potential to reduce costs significantly

  22. Finding the perfect cut-off for sensitive Troponin Best specificity at high sensitivity 99th percentile:  10% NSTEMI undetected 99th percentile Best sensitivity at high specificity 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 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 CollCardiol 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. The (fundamental) issue of NEJM trial resultssimplified simulation for insensitive Tn assays Diagnosis (insensitive Tn) Tn at baseline t0 t1  pat. 1 NSTEMI  pat. 2 other  pat. 3 NSTEMI cut off Tn pat. 4  NSTEMI  other pat. 5 Comparing insensitive Tn at baseline with Gold Standard Diagnosis Results of Gold Standard Diagnosis using insensitive Tn assays

  26. The (fundamental) issue of NEJM trial resultssimplified simulation for insensitive vs. sensitive Tn assays Diagnosis (insensitive Tn) Tn at baseline Tn sens at baseline t0 t1   pat. 1 NSTEMI   pat. 2 other   pat. 3 NSTEMI cut off Tn pat. 4   NSTEMI cut off Tn   other pat. 5 Part I: patient profiles that remain unchanged ! No change

  27. The (fundamental) issue of NEJM trial resultssimplified simulation for insensitive vs. sensitive Tn assays Diagnosis (insensitive Tn) Tn at baseline Tn sens at baseline t0 t1 improves Tn sens performance   pat. 6 NSTEMI cut off Tn   pat. 7 other worsens Tn sens performance if cut off is chosen too low   pat. 8 other other   pat. 9 cut off Tn   pat. 10 other No additional NSTEMI observable that are sensitive Tn negative Part II: additional patient profiles!

  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. The (fundamental) issue of NEJM trial resultssimplified simulation for future Gold Standard Diagnosis Tn sens at baseline, new diagn. Tn sens at baseline, old diagn. Diagnosis (insensitive Tn) Diagnosis (sensitive Tn) t0 t1   pat. 6 NSTEMI NSTEMI cut off Tn   pat. 7 other NSTEMI   pat. 8 other other  other NSTEMI  pat. 9 cut off Tn   pat. 10 other NSTEMI Results not predictable Part III: Gold Standard Diagnosis using sensitive Tn

  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 CollCardiol 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 orsensitive Tn) • together with a • negative Copeptin as AMI rule out (reason: low number of AMI)

  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 ~5% ~15% Need to wait for 2nd Tn ~80% ~5% ~15% 2nd Tn ~20-40% ~40-60%

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