Original Contribution
Copeptin Levels in Patients With Acute Ischemic
Stroke and Stroke Mimics
Matthias Wendt, MD; Martin Ebinger, MD; Alexander Kunz, MD; Michal Rozanski, MD;
Carolin Waldschmidt, MD; Joachim E. Weber, MD; Benjamin Winter, MD;
Peter M. Koch, MD; Christian H. Nolte, MD; Sabine Hertel, PhD; Tim Ziera, PhD;
Heinrich J. Audebert, MD; for the STEMO Consortium
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Background and Purpose—Copeptin levels are increased in patients diagnosed with stroke and other vascular diseases.
Copeptin elevation is associated with adverse outcome, predicts re-events in patients with transient ischemic attack and
is used in ruling-out acute myocardial infarction. We evaluated whether copeptin can also be used as a diagnostic marker
in the prehospital stroke setting.
Methods—We prospectively examined patients with suspected stroke on the Stroke Emergency Mobile—an ambulance
that is equipped with computed tomography and point-of-care laboratory. A blood sample was taken from patients
immediately after arrival. We analyzed copeptin levels in patients with final hospital-based diagnosis of stroke or stroke
mimics as well as in vascular or nonvascular patients. In addition, we examined the associations of symptom onset with
copeptin levels and the prognostic value of copeptin in patients with stroke.
Results—Blood samples of 561 patients were analyzed. No significant differences were seen neither between cerebrovascular
(n=383) and other neurological (stroke mimic; n=90) patients (P=0.15) nor between vascular (n=391) and nonvascular
patients (n=170; P=0.57). We could not detect a relationship between copeptin levels and time from onset to blood draw.
Three-month survival status was available in 159 patients with ischemic stroke. Copeptin levels in nonsurviving patients
(n=8: median [interquartile range], 27.4 [20.2–54.7] pmol/L) were significantly higher than in surviving patients (n=151:
median [interquartile range], 11.7 [5.2–30.9] pmol/L; P=0.024).
Conclusions—In the prehospital setting, copeptin is neither appropriate to discriminate between stroke and stroke mimic
patients nor between vascular and nonvascular patients.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01382862. The Pre-Hospital
Acute Neurological Therapy and Optimization of Medical Care in Stroke Patients study (PHANTOM-S) was registered
(NCT01382862). This sub-study was observational and not registered separately, therefore. (Stroke. 2015;46:00-00.
DOI: 10.1161/STROKEAHA.115.009877.)
Key Words: biomarkers ◼ copeptin ◼ myocardial infarction ◼ stroke ◼ vascular diseases
S
pecific treatment of patients with stroke requires rapid diagnosis in emergency care. It is necessary to exclude important differential diagnoses, usually called stroke mimics. Stroke
mimics are diseases with symptoms frequently seen in patients
with stroke but caused by noncerebrovascular pathogeneses.
Important stroke mimics are paresis and speech arrest during
or after epileptic seizures, migraine with aura, acute inflammatory diseases of the central nervous system, and metabolic or
dissociative disorders. A biomarker that differentiates between
strokes and stroke mimics would be very useful in the emergency setting but is missing so far. Copeptin, the C-terminal
part of the arginine vasopressin precursor is stoichiometrically
generated and has a good correlation to arginine vasopressin
but is more stable in the circulation and easy to determine.1
Copeptin mirrors the activation of the endogenous stress system. Copeptin elevations were found in critically ill patients
with sepsis and multiple traumas,2,3 in acute myocardial infarction,4,5 in patients with chronic heart failure,6 and in patients
with acute stroke.7,8 In patients with stroke, copeptin elevation
has been shown to be an independent predictor of poor functional outcome and mortality.7,9–11 Consideration of copeptin
improves the prognostic value of the National Institute of
Health Stroke Scale (NIHSS) and it predicts re-events in
patients with transient ischemic attack.11,12 Copeptin is released
Received April 30, 2015; final revision received June 30, 2015; accepted July 7, 2015.
From the Department of Neurology (M.W., M.E., A.K., M.R., C.W., J.E.W., B.W., P.M.K., C.H.N., H.J.A.) and Center for Stroke Research Berlin
(M.E., M.R., H.J.A.), Charité-Universitätsmedizin Berlin, Berlin, Germany; and Department for Clinical Diagnostics, Thermo Fisher Scientific (BRAHMS
GmbH), Hennigsdorf, Germany (S.H., T.Z.).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.​
009877/-/DC1.
Correspondence to Matthias Wendt, MD, Department of Neurology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm
30, 12203 Berlin, Germany. E-mail [email protected]
© 2015 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.115.009877
1
2 Stroke September 2015
shortly after acute vascular events.13 Increased copeptin levels
were found in patients with acute myocardial infarction even
when troponin T was still negative.14 In combination with highsensitive troponin T, copeptin has valid properties ruling-out
acute myocardial infarction15 and thereby, helps to identify
patients with chest pain who can be discharged home from
the emergency department without increased risk for major
adverse coronary events.16
In this study, we assessed copeptin levels in a prehospital setting of hyperacute stroke care on a specialized stroke
ambulance and examined its value in discriminating between
strokes and stroke mimics as well as between vascular and
nonvascular diagnoses.
Table 1. Copeptin Levels of Diagnostic Categories
Diagnoses
No. of
Patients (n)
Copeptin, pmol/L
Median (min–max)
Delirium
6
7.0 (2.5–80.7)
Inflammatory or demyelinating
diseases of the CNS
2
13.0 (6.8–19.2)
Movement disorder
3
4.2 (2.0–4.8)
Epilepsy
22
17.6 (<1.0–187.8)
Headache
13
2.8 (<1.0–8.1)
Transitory global amnesia
2
7.2 (6.0–8.3)
Sleeping disorders
1
2.5
Mononeuropathy
3
9 (2.9–32.8)
Polyneuropathy
1
33.1
Other neurological diagnoses
3
5.4 (3.8–8.8)
Patients
Retinal or optical nerve disorder
1
22.8
The Pre-Hospital Analysis and Triage of Acute Stroke and Stroke Like
Syndromes With Biomarkers study (PHANTAS-B) was conducted as
a parallel study of the Pre-Hospital Acute Neurological Therapy and
Optimization of Medical Care in Stroke Patients study (PHANTOM-S)
that investigated the effects of a specialized Stroke Emergency Mobile
Unit on hyperacute treatment in patients with stroke.17 The study
was integrated in the emergency medical system of Berlin, Germany
(NCT01382862).18 Stroke Emergency Mobile was deployed by the dispatch center when a previously validated stroke identification algorithm
indicated a suspected acute stroke.19 The stroke identification algorithm
at the dispatch center had demonstrated a sensitivity of 53% for stroke
and a positive predictive value of 59% for stroke and transient ischemic attack. Between June 2011 and May 2013, we included consecutive patients with informed consent who received Stroke Emergency
Mobile care. Discharge diagnoses were collected from all participating
hospitals. Vital status and modified Rankin Scale score at 3 months
was collected in ischemic stroke patients with thrombolytic treatment.
Oculomotor nerve palsy
1
1.9
Vestibular disorders
6
Subdural hematoma
2
77.1 (13.1–141.0)
Neuromuscular disorders
2
168.3 (11.0–325.7)
Neurocognitive disorders
10
6.3 (2.3–675.2)
Traumatic brain injury
2
202.7 (10.4–395.0)
Intoxication
2
8.3 (<1.0–16.1)
Syncope
6
88.0 (5.4–746.0)
Methods
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Blood Sampling and Analysis
Blood samples were taken immediately after arrival at scene before
any treatment was administered. They were centrifuged with 3000×g
for 15 minutes. Centrifugation was performed referring to a standardized clinical protocol. The reliability of this procedure conforms to
plasma isolated in a laboratory. After filling in a cryotube, plasma samples were stored at 4°C in the ambulance. After arriving at the emergency medical system station (maximum 8 hours after sampling), they
were frozen at −20°C. Frozen samples were shipped to the core laboratory facility of ThermoFisher Biomarkers (Thermo Fisher Scientific,
Clinical Diagnostics, BRAHMS GmbH, Hennigsdorf, Germany) for
analysis in a blinded and randomized fashion. Copeptin was measured
from EDTA plasma using the BRAHMS copeptin us KRYPTOR immunofluorescent assay with an analytical detection limit of <1 pmol/L
and a functional assay sensitivity of 1.8 pmol/L. The direct detection
range was 1.8 to 500 pmol/L and the extended, involving automatic
dilution, was ≤2000 pmol/L. Copeptin levels of individual patient
samples were measured in single determinations. In case determined
levels were below the functional assay sensitivity, conformational determinations were performed. Repeated measurements confirmed initial determinations with a coefficient of variation of 5%.
Documentation of Clinical Data
We used the data of the PHANTOM-S study. Time of symptom onset, time of blood sampling, clinical symptoms, results of computed
tomographic imaging, and point of care laboratory in the ambulance
were documented in the onsite Stroke Emergency Mobile documentation system. Final diagnoses of acute in-hospital care were collected as
International Classification of Diseases, Tenth Revision (ICD-10) codes
from all hospitals that participated in the PHANTOM-S study. Copeptin
laboratory results were merged with clinical data using pseudonyms.
Ischemic stroke
216.7 (3.8–544.5)
287
37.5 (<1.0–889.3)
Intracerebral hemorrhage
17
10.3 (3.3–669.1)
Subarachnoid hemorrhage
1
1.3
Transitory ischemic attack
74
9.5 (<1.0–345.3)
Other CVDs
4
5.9 (3.2–22.7)
Acute coronary syndrome
2
211.1 (22.5–399.7)
Infection
5
27.2 (4.9–63.8)
Tumor
8
9.3 (2.7–64.6)
75
23.3 (<1.0–545.6)
561
…
Other non-CVDs
CNS indicates central nervous system; and CVD, cerebrovascular diagnoses.
Categorization of Hospital Diagnoses
The following ICD-10 codes were categorized as acute cerebrovascular events: G45.x (except G45.4), I60.x I61.x, I63.x, I64.x. Other
neurological diagnoses that lead to emergency care and hospital
admission were classified as stroke mimics including the following
ICD-10 codes: A8.x, A35.x, C70.x, C71.x, C72.x, F0.x, F1.x, G0.x,
G1.x, G2.x, G5.x, G6.x, G7.x, G8.x, G9.x, G30.x, G31.x, G32.x,
G35.x, G36.x, G40.x, G41.x, G42.x, G43.x, G44.x, G45.4x, G47.x,
G48.x, H34.x, H46.x, H48.x, H49.x, H50.x, H51.x, H52.x, H53.x,
H54.x, H81.x, I62.x, I69.x, R4.x, R25.x, R26.x, R27.x, R28.x, R29.x,
R55.x, S0.x, T3.x, T4.x, T5.x, T60.x, T61.x, T62.x, T63.x, T64.x,
T65.x. Vascular diseases comprised the following ICD-10 codes:
D65.1x, D68.3x, G45.x (except G45.4), G46.x, H34.x, I6.x, I20.x,
I21.x, I22.x, I23.x, I24.x, I26.x, I60.x, I61.x, I63.x, I64.x, I65.x,
I66.x, I67.x, I68.x, I69.x, I71.0x, I71.1x, I71.3x, I71.5x, I71.8x,
I72.x, I74.x, I77.2x, K55.0x, R02.x, and R04.x. All other ICD-10
codes were classified as nonvascular events. For description of the
diagnostic spectrum, we categorized the diagnosis in diagnostic
subgroups (Table 1; Table I in the online-only Data Supplement).
Noncerebrovascular diagnoses (non-CVDs) that were coded in 1 patient only were subsumed under other non-CVDs.
Wendt et al Copeptin Levels in Strokes and Stroke Mimics 3
Table 2. Patient Characteristics of Vascular and Nonvascular Patients
Vascular Patients (n=391)
Nonvascular Patients (n=170)
P Value
Demographics
Age, y, mean (SD)
74.3 (12.3)
68.9 (15.8)
Sex, male, n (%)
169 (43.2)
90 (52.9)
<0.01
Atrial fibrillation, n (%)
126 (32.2)
26 (15.3)
<0.01
Diabetes mellitus, n (%)
95 (24.3)
46 (27.1)
0.49
Time last-well-seen to
blood sampling, min, median (IQR)
72 (38–322)
74 (42–245)
0.45
12.1 (5.3–30.3)
12.1 (4.8–57.4)
0.57
0.034
Risk factors
Copeptin level, pmol/L, median (IQR)
IQR indicates interquartile range.
Statistical Analysis
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We used the Mann–Whitney U test for comparisons of copeptin levels
in the different diagnostic categories, and vital status at 3 months. For
graphical and statistical comparisons of copeptin levels, we performed
a logarithmic transformation (log 10) to reduce skewness. A P<0.05
was considered as statistically significant. For comparison of copeptin levels and time to taking blood samples, we used the following
categories: 15–30 minutes, 31–60 minutes, 61–90 minutes, 91–120
minutes, 121–180 minutes, and >180 minutes. We used the Spearman
correlation test for comparison of copeptin levels with times to blood
sampling, NIHSS and age, and illustrated copeptin levels in different
time and NIHSS categories. Good outcome was defined as a modified Rankin Scale score ≤1 and bad outcome as a modified Rankin
Scale score >1. The odds for good and bad outcome according to copeptin levels were calculated and were adjusted for NIHSS and age.
Statistical analyses were performed in SPSS version 22.
Ethics Approval
The study was approved by the Data Protection Commissioner and
the Ethics Committee of the Charité Universitätsmedizin Berlin.
Documentation was done with pseudonyms. Data were analyzed only
if patients or legally authorized representatives had given informed
consent on the use of individual blood material and clinical data.
Results
From June 2011 to May 2013, we collected samples from a
total of 576 patients. Fifteen patients had to be excluded
because of missing information about final diagnosis. Copeptin
levels (pmol/L) according to diagnoses are shown in Table 1.
Diagnostic categories according to ICD-10 codes are shown
in Table I in the online-only Data Supplement. Table 2 shows
patient characteristics of vascular and nonvascular patients.
Characteristics of stroke and stroke mimic patients are shown
in Table 3. We compared copeptin levels of cerebrovascular
(n=383) patients (ischemic stroke, hemorrhagic stroke, transient ischemic attack, and non-specified cerebrovascular diseases) with levels of stroke mimic patients (n=90; Figure 1).
In a second analysis, we compared copeptin levels of vascular patients (n=391) and levels of nonvascular patients (n=170;
Figure 1). We found no significant differences in copeptin levels
neither between stroke and stroke mimic patients (P=0.15) nor
between ischemic and hemorrhagic stroke patients (P=0.60)
nor between vascular and nonvascular patients (P=0.57). Only
5 patients died during in-hospital stay. They had nonsignificantly higher copeptin levels compared with surviving patients
(median, 30.5 pmol/L; interquartile range [IQR], 10.4–185
pmol/L versus 12.0 pmol/L; IQR, 5.2–34 pmol/L; P=0.15).
The 3-month survival status of patients with ischemic stroke
was collected from 159 patients. We examined the prognostic
value of copeptin and compared copeptin levels of surviving
(n=151) and nonsurviving (n=8) patients. These 8 nonsurviving patients include the 5 patients, who died during in-hospital stay. Significantly higher copeptin levels in nonsurviving
patients (median, 27.4 pmol/L; IQR, 20.2–54.7 pmol/L) were
found compared with surviving patients (median, 11.7 pmol/L;
IQR, 5.2–30.9 pmol/L; P=0.024). However, stroke severity
(NIHSS, 18.5 versus 6.0; P<0.001) and age (83.0 versus 73.0
Table 3. Patient Characteristics of Stroke and Stroke Mimic Patients
Stroke/TIA Patients (n=383)
Stroke Mimic Patients (n=90)
P Value
Demographics
Age, y, mean (SD)
74.1 (12.3)
66.0 (18.1)
<0.01
Sex, male, (n, %)
168 (43.9)
43 (47.8)
0.50
Atrial fibrillation (n, %)
121 (31.6)
15 (16.7)
<0.01
Diabetes mellitus (n, %)
93 (24.3)
22 (24.4)
0.97
Time last-well-seen to blood
sampling, median (IQR)
72 (38–333)
65 (38–172)
0.19
Risk factors
NIHSS, median (IQR)*
Copeptin level, pmol/L, median (IQR)
4 (1–7)
11.5 (5.3–29.3)
1 (0–6)
8.2 (3.3–32.8)
IQR indicates interquartile range; NIHSS, National Institute of Health Stroke Scale; and TIA, transient ischemic attack.
*Available for 376 patients with stroke/TIA and 78 stroke mimic patients.
<0.01
0.15
4 Stroke September 2015
Figure 1. Boxplots of copeptin levels (logarithm) of stroke vs non-stroke patients (A) and vascular vs nonvascular patients (B).
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years; P=0.008) were also significantly higher in nonsurviving
patients compared with surviving patients. Modified Rankin
Scale score was available in 141 patients. Logarithmic transformed copeptin levels were not an independent predictor
for bad outcome (odds ratio, 0.74; 95% confidence interval,
0.40–1.45; P=0.41). There was no association between time
from symptom onset and copeptin levels neither for all patients
(Spearman ρ, 0.007) nor for the subgroup of patients with ischemic stroke (Spearman ρ, −0.024; Figure 2). There were significantly higher levels of copeptin in patients with higher stroke
severity (NIHSS 0–5: median, 9.6 pmol/L and IQR, 5.2–21.6;
NIHSS 6–10: median, 12.8 pmol/L and IQR, 6.4–33.5; NIHSS
11–15: median, 21.1 pmol/L and IQR, 7.0–38.0; NIHSS 16–20:
median, 32 pmol/L and IQR 11.6–77.7; NIHSS >20: median,
87.1 pmol/L and IQR, 21.6–382; Spearman ρ, 0.275; P<0.01).
There was no significant association between copeptin levels
and age (Spearman ρ, 0.074; P=0.23).
Discussion
In our study, copeptin levels obtained before hospital arrival
did neither discriminate between stroke and stroke mimic
patients nor between vascular and nonvascular patients. As
copeptin elevation seems to relate to the severity of stroke or
of other cardiovascular events,7 we had assumed that it might
also discriminate between stroke and stroke mimics as well as
between vascular and nonvascular events. Contrary to these
considerations, our results did not show significant differences
in copeptin levels between these groups of patients. Copeptin
was elevated within the first minutes after the event, but there
was no correlation between copeptin levels and time from
symptom onset to drawing blood samples. Higher copeptin
levels were associated with increased mortality in patients
with stroke in unadjusted analysis. As we could not perform
multivariable regression for the small event rate, we cannot
conclude that high copeptin levels have an independent prognostic value. Nevertheless, the prognostic value for patients
with stroke is in line with previous observations7,9–11 and a
Figure 2. Boxplots of copeptin levels (logarithm) and time to blood sample of all patients (A) and patients with ischemic stroke (B).
Wendt et al Copeptin Levels in Strokes and Stroke Mimics 5
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recently published study showing an association of copeptin
with stroke occurrence after transient ischemic attack.20 The
prognostic property of copeptin with regard to mortality and
morbidity was also shown in patients with other cardiovascular events.4,21,22 In our analysis, copeptin elevation occurred in
a wide range of diagnoses, most likely induced by an activation of the endogenous stress system. Previous studies found
an elevation in other nonvascular diseases, too.23,24 Copeptin is
released rapidly after hemodynamic stress.13,14 In our patients,
we found no influence of the interval from symptom onset to
blood sampling on copeptin levels. Although we cannot rule
out that copeptin was elevated before the event, this result suggests an immediate secretion, within the first minutes after
developing symptoms. Therefore, copeptin is obviously not an
appropriate marker to indicate time to stroke onset. Strengths
of our study are the relatively high number of patients as well
as the very early examination on an ambulance. To our knowledge, it is the first study that examined copeptin as a potential
biomarker for discrimination between strokes and stroke mimics in the prehospital setting. Although the statistical results
of our study were negative, we have shown that prospective
blood sampling, and centrifugation and biomarker research are
feasible in the prehospital setting without causing time delays
in patient care. A limitation of the study is the unequal distribution of differential diagnoses. The PHANTOM-S study was
focused on patients with stroke. As a consequence, the number
of nonvascular patients was smaller than the number of vascular patients. Furthermore, we collected information about
vital status at 3 months in patients with ischemic stroke only
because the aim of our study was not an outcome analysis and
the study methodology did not allow the collection of longterm outcome in other patients groups.
Conclusions
Copeptin is released at an early stage after onset of acute diseases. In our study, it did not discriminate between strokes and
stroke mimics or between vascular and nonvascular diseases
in the prehospital setting.
Acknowledgments
We thank all participating paramedics and radiographers for outstanding team work. We are grateful to Kerstin Bollweg for data collection
and management in co-operating hospitals. We thank Ulrike Grittner
for statistical support. STEMO Consortium: Berliner Feuerwehr,
Berlin, Germany; BRAHMS GmbH, Hennigsdorf, Germany;
Charité—Universitätsmedizin Berlin, Berlin, Germany; MEYTEC
GmbH, Werneuchen, Germany.
Sources of Funding
The study was part of the Pre-Hospital Acute Neurological Treatment
and Optimization of Medical care in Stroke study (PHANTOM-S).
PHANTOM-S was funded by the Zukunftsfonds Berlin (Berlin
Innovation Fund) and the Technology Foundation Berlin with
European Union co-financing by the European Regional Development
Fund. The study received support for research from the Center for
Stroke research Berlin within the funding of the Federal Ministry
for Education and Research (BMBF). The study was conducted in
cooperation with Thermo Fisher Scientific (BRAHMS GmbH).
Thermo Fisher Scientific (BRAHMS GmbH) was part of the STEMO
Consortium and was involved in the design of the biomarker study but
had no role in the funding of the study, collection, and analysis of the
blood samples. Biochemical analyses of copeptin were conducted in
the Thermo Fisher Scientific laboratories in Hennigsdorf, Germany.
Disclosures
Drs Hertel and Ziera are employees of Thermo Fisher Scientific
(BRAHMS GmbH), the manufacturer of the assay. Dr Audebert
received research grant from Berlin Innovation Fund and German
Federal Ministry for Education and Research. Dr Audebert reports
receiving speaker honoraria from Boehringer Ingelheim, EVER
Neuropharma, Pfizer, BMS, Strehlows GmbH, and speaker and consultancy honoraria from Lundbeck A/S, Pfizer, Sanofi, and Roche
Diagnostics. The other authors report no conflicts.
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Copeptin Levels in Patients With Acute Ischemic Stroke and Stroke Mimics
Matthias Wendt, Martin Ebinger, Alexander Kunz, Michal Rozanski, Carolin Waldschmidt,
Joachim E. Weber, Benjamin Winter, Peter M. Koch, Christian H. Nolte, Sabine Hertel, Tim
Ziera and Heinrich J. Audebert
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Stroke. published online August 6, 2015;
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SUPPLEMENTAL MATERIAL
Supplemental Table I: Diagnostic categories according ICD 10 codes
Diagnoses
CNS virus infection
CNS malignoma
Delirium
Inflammatory or demyelinating diseases
of the CNS*
System atrophy
Movement disorder
Other degenerative diseases of the CNS
Epilepsy
Headache
Transitory global amnesia
Sleeping disorders
Mononeuropathy
Polyneuropathy
Other neurological diagnoses
Retinal or optical nerve disorder
Oculomotor nerve palsy
Visual impairment / blindness
Vestibular disorders
Subdural hematoma
Neuromuscular disorders
Neurocognitive disorders
Residual deficits after stroke
Neuromuscular syndromes
Neurocognitive syndromes
Traumatic brain injury
Intoxication
Syncope
Ischemic stroke
Intracerebral hemorrhage
Subarachnoid hemorrhage
Transitory ischemic attack
Other CVD**
Acute coronary syndrome
Infection
Tumor (non CNS)
Other non-CVD**
Number
of patients (N)
0
0
6
2
ICD-10
A8
C70-C72
F0, F1
G0, G35-G36
0
3
0
22
13
2
1
3
1
3
1
1
0
6
2
2
10
0
0
0
2
2
6
287
17
1
74
4
2
5
8
75
G1
G2
G30-G32
G40-G41
G43-G44
G45.4
G47
G5
G6
A 35, G9, G48, G42
H34, H47, H48
H49, H52
H53, H54
H81
I62
G7
G8
I69
R25-R29
R4
S0
T3-T5, T61-T65
R55
I63
I61
I60
G45
I64
I20-I24, I26
A0-B99#
C0-C99#
All others
561
*CNS: central nervous system, **CVD: cerebrovascular diagnoses, #if not included in above
categories!