june 2010 copeptin in acute myocardial infarction – background & clinical data
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June 2010
Copeptin in Acute Myocardial Infarction – Background & Clinical Data
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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
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What is Vasopressin (Copeptin) and where does it come from?
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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
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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
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What is the physiological role of Vasopressin?
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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
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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
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Vasopressin in stress situationVasopressin in stress situation
ACTH
AVP
STRESS
Cortisol
Myocardial infarction
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Why not simply measure Vasopressin?
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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)
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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)
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Is Copeptin produced together with Vasopressin?
Show both analytes the same kinetics in vivo?
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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
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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
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Which Copeptin levels should be expected in Normals?
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Morgenthaler NG et al., Clin Chem. 2006 Jan;52(1):112-9
Normal distribution
Copeptin is not age-relatedCopeptin is not age-related
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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
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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
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What may clinicians ask when you talk about Vasopressin / Copeptin?
disturbed Vasopressin / Copeptin secretion and water / salt balance?
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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
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100% sensitivity – 100% specificityCopetin level < 4.75 pmol/L
Diagnosis of diabetes insipidusDiagnosis of diabetes insipidus
Katan et al. JCEM 2007
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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
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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
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Assay Assay PerformancePerformance
What about the performance of the KRYPTOR assay?
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Copeptin assay parametersCopeptin assay parameters
Data taken from IFU (instructions for use)
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Assay Assay PerformancePerformance
Copeptin in early rule out of myocardial infarction
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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
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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+
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Proof of concept studyProof of concept study
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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
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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%)
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Reichlin et al. J Am Coll Cardiol 2009;54:60-8
Copeptin levels at Copeptin levels at presentationpresentation
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Reichlin et al. J Am Coll Cardiol 2009;54:60-8
Copeptin and Troponin levels at presentationCopeptin and Troponin levels at presentation
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ROC curves at presentationROC curves at presentation
Reichlin et al. J Am Coll Cardiol 2009;54:60-8
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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
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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
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•
Paper submitted, confidential Data
Validation studyValidation study
Keller et al. J Am Coll Cardiol 2010;55:2096-2106.
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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.
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Baseline characteristicsBaseline characteristics
+ 211
+ 289
Keller et al. J Am Coll Cardiol 2010;55:2096-2106.
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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.
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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.
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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.
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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
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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.
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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
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ConclusionConclusion
Keller et al. J Am Coll Cardiol 2010;55:2096-2106.