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June 2010

Copeptin in Acute Myocardial Infarction – Background & Clinical Data. June 2010. Vasopressin & Copeptin - FAQs. What is Vasopressin (Copeptin) and where does it come from? What is the physiological role of Vasopressin? Why not simply measure Vasopressin?

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June 2010

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  1. Copeptin in Acute Myocardial Infarction – Background & Clinical Data June 2010

  2. Vasopressin & Copeptin - FAQs • What is Vasopressin (Copeptin) and where does it come from? • What is the physiological role of Vasopressin? • Why not simply measure Vasopressin? • Is Copeptin produced together with Vasopressin? Do both analytes show the same kinetics? • Which Copeptin levels should be expected in Normals? • What may clinicians ask when you talk about Copeptin (Vasopressin)? • What about the performance of the Copeptin KRYPTOR assay? • Copeptin in early rule out of myocardial infarction

  3. What is Vasopressin (Copeptin) and where does it come from?

  4. Structure of Vasopressin O NH2 O NH2 -C • Arginine-Vasopressin (AVP) • synonym: Vasopressin or antidiuretic hormone (ADH) • peptide hormone • 9 amino acids • Disulfide bridge between two cysteine amino acids • C-terminal amidation NH2-

  5. Synthesis of Vasopressin • Synthesis as a precursor hormone (pre-pro-vasopressin) in the hypothalamus • Cleavage and transport in granules • down the axons • Storage in granules in the posterior pituitary • Release into nearby capillaries upon • appropriate stimulation Figures adapted from: Golenhofen, Basislehrbuch Physiologie, Urban & Fischer; and Morgenthaler NG et al.: Clin Chem 2006 Information: Russel IC and Glover PJ: Critical Care and Resuscitation 2002; Ranger GS: IJCP 2002; Oghlakian G and Klapholz M: Cardiology in Review 2009

  6. What is the physiological role of Vasopressin?

  7. Vasopressin - physiological role Main role: Regulation of water balance - Increased plasma osmolality - Decreased arterial circulating volume AVP: acts via V2-receptors in the kidney -> water retention AVP: Synthesis in the Hypothalamus Figure adapted from: Knoers NV N Engl J Med. 2005 May 5;352(18):1847-50

  8. Vasopressin (AVP) effects • Effects of AVP dependent on concentration : • maximal antidiuretic effect: below 15 pg/ml • vasoconstrictor effect at higher concentrations • very little effect on blood pressure at physiological levels! Singh Ranger G, Int J Clin Pract 2002; 56(10):777-782

  9. Vasopressin in stress situation Myocardialinfarction STRESS AVP ACTH Cortisol

  10. Why not simply measure Vasopressin?

  11. Protease Vasopressin Vasopressin Receptor Vasopressin Vasopressin Platelets Quantification of Vasopressin is difficult Further problem: very unstable ex vivo (even frozen) Only specialized labs measure AVP (time to results several days) Not a single FDA approved AVP assay on the market LIMITED CLINICAL USE

  12. Signal Peptidase ProhormoneConvertase Vasopressin Prohormone processing and assay Signal Vasopressin Copeptin Neurophysin II Vasopressin Copeptin Neurophysin II Neurophysin II Copeptin very stable ex vivo Fast assay (KRYPTOR) Copeptin Morgenthaler NG et al., Clin Chem. 2006

  13. Is Copeptin produced together with Vasopressin? • Show both analytes the same kinetics in vivo?

  14. Correlation of Vasopressin and Copeptin LIA Assay r = 0.78 Jochberger S et al., Schock 2009 31: 132-138 Validation in: Jochberger S et al., Intensive Care Med 2009 35:489-497 Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9.

  15. Copeptin – like Vasopressin – is rapidly degraded in vivo 97.5 % percentile KRYPTOR: 17.4 pmol/L t1/2: few minutes Morgenthaler et al. Clin Chem 2006

  16. Which Copeptin levels should be expected in Normals?

  17. Copeptin is not age-related Normal distribution Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9

  18. Copeptin levels dependent on gender Significantly higher levels in males 706 healthy volunteers Bhandari SS et al, Clinical Science (2009) 116, 257–263

  19. Copeptin: Influence of exercise 97.5 % pecentile KRYPTOR: 17.4 pmol/L Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9

  20. What may clinicians ask when you talk about Vasopressin / Copeptin? • disturbed Vasopressin / Copeptin secretion and water / salt balance?

  21. Diagnosis of diabetes insipidus 38 patients (33 after transphenoidal surgery, 5 without surgery) n = 29 normal posterior pituitary function n = 9 diabetes insipidus centralis insulin-induced hypoglycemia test  Glucose < 2 mmol/l Katan et al. JCEM 2007

  22. Diagnosis of diabetes insipidus 100% sensitivity – 100% specificity Copetin level < 4.75 pmol/L Katan et al. JCEM 2007

  23. Diagnosis of diabetes insipidus Diabetes Insipidus is no indication for the KRYPTOR Assay! FAS Kryptor Katan et al. JCEM 2007

  24. Hyponatremia • most common fluid and electrolyte disturbance • prevalence: 15-30% of hospitalized patients • variety of disorders causing hyponatremia - treatment varies widely Fenske et al.: J Clin Endocrinol Metab, 2009

  25. Assay Performance • What about the performance of • the KRYPTOR assay?

  26. Copeptin assay parameters Data taken from IFU (instructions for use)

  27. Assay Performance • Copeptin in early rule out • of myocardial infarction

  28. Background • Chest pain patients about 10% of ED consultations • Cardiac Troponin current diagnostic gold standard • Troponin retesting after 6-8 hours necessary due to delayed increase • Rapid and reliable rule out of acute MI already at presentation is a large unmet clinical need

  29. Hypothesis Combination of + Cardiac Necrosis Troponin Endogenous Stress Copeptin • rapid and accurate rule out of AMI • at initial presentation • without Tn retesting after 6 to 8 hours

  30. Proof of concept study

  31. Methods • Consecutive pts with chest pain <12h • Observational study • Serial blood sampling: 0h,1h, 2h, 3h, 6h • Follow up 90d, 360d, 720d • Adjudicated Diagnosis: • 2 independent experts • using all clinical information within 60d FU • (History, physical examination, ECG, cTn, chest x-ray, • echo, coronary angiography, exercise testing (MPS), • CT-scans, endoscopy, ....) • Blinded for investigational biomarkers

  32. Adjudicated final diagnoses Chest pain of unknown origin (9%) Myocardial Infarction (17%) • Thereof • STEMI (37%) • NSTEMI (63%) Unstable Angina (16%) Non-coronary cardiac chest pain (13%) Non-cardiac chest pain (46%)

  33. Copeptin levels at presentation Reichlin et al. J Am Coll Cardiol 2009;54:60-8

  34. Copeptin and Troponin levels at presentation Reichlin et al. J Am Coll Cardiol 2009;54:60-8

  35. ROC curves at presentation Reichlin et al. J Am Coll Cardiol 2009;54:60-8

  36. Rapid rule out of AMI at presentation 314 = 65% (cTnT / Copeptin negative) 487 pts 173 = 35% (cTnT / Copeptin positive) Reichlin et al. J Am Coll Cardiol 2009;54:60-8

  37. Conclusion Copeptin significantly improves the early diagnosis of AMI (AUC for combination with Troponin T 0.97). The combination of Copeptin and Troponin T allows a rule out of AMI at presentation with a sensitivity of 98.8% and a NPV of 99.7%. The use of Copeptin in conjunction with Troponin T, ECG and clinical findings may obviate the need for prolonged stay in the ED and Troponin retesting after 6 to 8 hours in two-thirds of patients.This change in clinical practice might result in significant medical and economic benefits.

  38. Validation study Paper submitted, confidential Data Keller et al. J Am Coll Cardiol 2010;55:2096-2106.

  39. Methods • 1386 patients with suspected acute coronary syndrome • Multicenter approach • Troponin T (4th generation Roche Diagnostics) used for Gold Standard Diagnosis • Diagnosis NSTEMI: • - one value above 0.03 ng/mL ! • - and a typical kinetic (rise or fall of at least 20%) Keller et al. J Am Coll Cardiol 2010;55:2096-2106.

  40. Baseline characteristics  + 289  + 211 Keller et al. J Am Coll Cardiol 2010;55:2096-2106.

  41. Final diagnosis 7% 15% 13% 65% Potential „rule out-portion“: ca. 78% Keller et al. J Am Coll Cardiol 2010;55:2096-2106.

  42. Time course of different markers Patients with time of chest pain onset < 2h MI: n=75 NCCP: n=213 Keller et al. J Am Coll Cardiol 2010;55:2096-2106.

  43. Diagnostic performance of Copeptin/Troponin T AUCs according to time of chest pain onset Paper in preparation for submission, confidential Data Keller et al. J Am Coll Cardiol 2010;55:2096-2106.

  44. Diagnostic performance (1) T=0 Copeptin + Troponin T • Best AUC • combination • Copeptin / Troponin T • 0.93 • TnT+ Myo: 0.91 • TnT + CKMB: 0.88 Keller et al. J Am Coll Cardiol 2010;55:2096-2106.

  45. Diagnostic performance (2) Keller et al. J Am Coll Cardiol 2010;55:2096-2106.

  46. Copeptin and sensitive Troponin *TnI > 0.04 ng/ml † Copeptin cut-off 13 pmol/l *Copeptin cut-off 9.8 pmol/l Keller et al. J Am Coll Cardiol 2010;55:2096-2106.

  47. Conclusion Keller et al. J Am Coll Cardiol 2010;55:2096-2106.

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