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

June 2010

Copeptin in Acute Myocardial Infarction – Background & Clinical Data

Vasopressin & Copeptin - FAQsVasopressin & 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

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

Structure of VasopressinStructure of Vasopressin

O

NH2

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

Synthesis of Vasopressin Synthesis of Vasopressin

Figures adapted from: Golenhofen, Basislehrbuch Physiologie, Urban & Fischer; and Morgenthaler NG et al.: Clin Chem 2006Information: Russel IC and Glover PJ: Critical Care and Resuscitation 2002; Ranger GS: IJCP 2002; Oghlakian G and Klapholz M: Cardiology in Review 2009

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

What is the physiological role of Vasopressin?

Vasopressin - physiological roleVasopressin - physiological role

AVP:acts via V2-receptors in the kidney

-> water retention

Main role: Regulation of water balance

Figure adapted from: Knoers NV N Engl J Med. 2005 May 5;352(18):1847-50

- Increased plasma osmolality - Decreased arterial circulating volume

AVP:Synthesis in the Hypothalamus

receptor location effect

V2 kidney water retention

V1a vascular smooth muscle cells

strong vasoconstriction

V1b endocrine cells (e.g. pituitary)

regulation of ACTH secretion during stress

Vasopressin (AVP) effectsVasopressin (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

Vasopressin in stress situationVasopressin in stress situation

ACTH

AVP

STRESS

Cortisol

Myocardial infarction

Why not simply measure Vasopressin?

Quantification of Vasopressin is difficultQuantification of Vasopressin is difficult

Vasopressin

PlateletsPlatelets

Vasopressin

ProteaseProtease

Vasopressin

Vasopressin

ReceptorReceptor

Only specialized labs measure AVP (time to results several days)Not a single FDA approved AVP assay on the market

LIMITED CLINICAL USE

Further problem: very unstable ex vivo (even frozen)

Morgenthaler NG et al., Clin Chem. 2006

Prohormone processing and assayProhormone processing and assay

SignalSignal VasopressinVasopressin Neurophysin IINeurophysin II CopeptinCopeptin

Copeptin very stable ex vivo

Fast assay (KRYPTOR)

Is Copeptin produced together with Vasopressin?

Show both analytes the same kinetics in vivo?

r = 0.78r = 0.78LIA

Assay

Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9.Jochberger S et al., Schock 2009 31: 132-138

Validation in: Jochberger S et al., Intensive Care Med 2009 35:489-497

Correlation of Vasopressin and CopeptinCorrelation of Vasopressin and Copeptin

700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 18000123456789

10111213141516

Copeptin male 45 y, BMI 23

Copeptin female 23 y, BMI 19water

food

day time (hours)

Co

pep

tin

(p

mo

l/L)

97.5 % percentile KRYPTOR:17.4 pmol/L

t1/2: few minutes

Copeptin – like Vasopressin – is rapidly degraded Copeptin – like Vasopressin – is rapidly degraded in vivo in vivo

Morgenthaler et al. Clin Chem 2006

Which Copeptin levels should be expected in Normals?

Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9

Normal distribution

Copeptin is not age-relatedCopeptin is not age-related

Bhandari SS et al, Clinical Science (2009) 116, 257–263

706 healthy volunteers

Significantly higher levels in males

Copeptin levels dependent on genderCopeptin levels dependent on gender

Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9

Copeptin: Influence of exerciseCopeptin: Influence of exercise

97.5 % pecentile KRYPTOR:17.4 pmol/L

What may clinicians ask when you talk about Vasopressin / Copeptin?

disturbed Vasopressin / Copeptin secretion and water / salt balance?

38 patients (33 after transphenoidal surgery, 5 without surgery)

n = 29 normal posterior pituitary function n = 9 diabetes insipidus centralis

Katan et al. JCEM 2007

Diagnosis of diabetes insipidusDiagnosis of diabetes insipidus

intact post. pituitary Diabetes insipidus0

5

10

15

20

25

p = 0.003

Basal Copeptin

Co

pep

tin

(p

mo

l/L)

intact post. pituitary Diabetes insipidus0

5

10

15

20

25 p < 0.001

Co

pep

tin

(p

mo

l/L)

Glucose < 2 mmol/l

insulin-induced hypoglycemia test

100% sensitivity – 100% specificityCopetin level < 4.75 pmol/L

Diagnosis of diabetes insipidusDiagnosis of diabetes insipidus

Katan et al. JCEM 2007

intact post. pituitary Diabetes insipidus0

5

10

15

20

25 p < 0.001C

op

epti

n (

pm

ol/L

)

FAS Kryptor

Diagnosis of diabetes insipidusDiagnosis of diabetes insipidus

Diabetes Insipidus is Diabetes Insipidus is no indication for the no indication for the

KRYPTOR Assay!KRYPTOR Assay!

Katan et al. JCEM 2007

HyponatremiaHyponatremia

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

Assay Assay PerformancePerformance

What about the performance of the KRYPTOR assay?

Copeptin assay parametersCopeptin assay parameters

Data taken from IFU (instructions for use)

Assay Assay PerformancePerformance

Copeptin in early rule out of myocardial infarction

BackgroundBackground

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

HypothesisHypothesis

rapid and accurate rule out of AMI • at initial presentation • without Tn retesting after 6 to 8 hours

Cardiac Necrosis Troponin

Combination of

Endogenous StressCopeptin+

Proof of concept studyProof of concept study

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

MethodsMethods

Adjudicated final diagnosesAdjudicated final diagnoses

Myocardial Infarction (17%)

Unstable Angina(16%)

Non-coronary cardiac chest pain (13%)

Non-cardiac chest pain (46%)

Chest pain of unknown origin (9%)

ThereofSTEMI (37%)NSTEMI (63%)

Reichlin et al. J Am Coll Cardiol 2009;54:60-8

Copeptin levels at Copeptin levels at presentationpresentation

Reichlin et al. J Am Coll Cardiol 2009;54:60-8

Copeptin and Troponin levels at presentationCopeptin and Troponin levels at presentation

ROC curves at presentationROC curves at presentation

Reichlin et al. J Am Coll Cardiol 2009;54:60-8

487 pts314 = 65% (cTnT / Copeptin negative)

173 = 35% (cTnT / Copeptin positive)

Rapid rule out of AMI at presentationRapid rule out of AMI at presentation

Reichlin et al. J Am Coll Cardiol 2009;54:60-8

1. Copeptin significantly improves the early diagnosis of AMI (AUC for combination with Troponin T 0.97).

2. 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%.

3. 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.

ConclusionConclusion

•

Paper submitted, confidential Data

Validation studyValidation study

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

MethodsMethods

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.

Baseline characteristicsBaseline characteristics

+ 211

+ 289

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

Final diagnosis Final diagnosis

65%

13%

7%15%

Potential „rule out-portion“: ca. 78%

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

Time course of different markersTime course of different markers

Patients with timeof chest pain onset < 2h

MI: n=75NCCP: n=213

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

Paper in preparation for submission, confidential Data

AUCs according to time of chest pain onset

Diagnostic performance of Diagnostic performance of Copeptin/Troponin TCopeptin/Troponin T

< 3h < 6h < 12h All

Troponin T 0.77 0.8 0.81 0.84

Copeptin 0.79 0.78 0.78 0.74

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

T=0

Diagnostic performance (1)Diagnostic performance (1)

Best AUC combination

Copeptin / Troponin T0.93

TnT+ Myo: 0.91TnT + CKMB: 0.88

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

Copeptin + Troponin T

Diagnostic performance (2)Diagnostic performance (2)

Troponin T(cut-off:

0.03 ng/mL)

Copeptin (cut-off:

13 pmol/L)

Combination

Sensitivity 62 58 88

Specificity 97 78 76

Positive predictive value 87 46 55

Negative predictive value 89 85 95

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

Copeptin and sensitive TroponinCopeptin and sensitive Troponin

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

*Copeptin cut-off 9.8 pmol/l † Copeptin cut-off 13 pmol/l *TnI > 0.04 ng/ml

ConclusionConclusion

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