Prognostic and diagnostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from the ACE 2 study
Winther et al. Respiratory Research
Prognostic and diagnostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from the ACE 2 study
Jacob A. Winther 0 1
Jon Brynildsen 0 1
Arne Didrik Høiseth 0 1
Heidi Strand 4
Ivar Følling 0 1
Geir Christensen 2
Ståle Nygård 3
Helge Røsjø 0 1
Torbjørn Omland 0 1
0 Institute of Clinical Medicine, University of Oslo , Oslo , Norway
1 Division of Medicine, Akershus University Hospital , Lørenskog , Norway
2 Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , Oslo , Norway
3 Bioinformatics Core Facility, Institute for Medical Informatics, Oslo University Hospital and University of Oslo , Oslo , Norway
4 Division of Diagnostics and Technology, Akershus University Hospital , Lørenskog , Norway
Background: Copeptin is a novel biomarker that predicts mortality in lower respiratory tract infections and heart failure (HF), but the diagnostic value of copeptin in acute dyspnea and the prognostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is not clear. Method: We determined copeptin and NT-proBNP concentrations at hospital admission in 314 patients with acute dyspnea who were categorized by diagnosis. Survival was registered after a median follow-up of 816 days, and the prognostic and diagnostic properties of copeptin and NT-proBNP were analyzed in acute HF (n = 143) and AECOPD (n = 84) separately. Results: The median concentration of copeptin at admission was lower in AECOPD compared to acute HF (8.8 [5. 2-19.7] vs. 22.2 [10.2-47.9]) pmol/L, p < 0.001), but NT-proBNP discriminated acute HF from non-HF related dyspnea more accurately than copeptin (ROC-AUC 0.85 [0.81-0.89] vs. 0.71 [0.66-0.77], p < 0.0001). Adjusted for basic risk factors, increased copeptin concentrations predicted mortality in AECOPD (HR per log (ln) unit 1.72 [95% CI 1.21-2. 45], p = 0.003) and acute HF (1.61 [1.25-2.09], p < 0.001), whereas NT-proBNP concentrations predicted mortality only in acute HF (1.62 [1.27-2.06], p < 0.001). On top of a basic model copeptin reclassified a significant proportion of patients into a more accurate risk strata in AECOPD (NRI 0.60 [0.19-1.02], p = 0.004) and acute HF (0.39 [0.06-0. 71], p = 0.020). Conclusion: Copeptin is a strong prognostic marker in both AECOPD and acute HF, while NT-proBNP concentrations predict mortality only in patients with acute HF. NT-proBNP levels are superior to copeptin levels to diagnose acute HF in patients with acute dyspnea.
Copeptin; NT-proBNP; COPD; Heart failure; Epidemiology; Dyspnea; Hyponatremia; Vasopressin; Antidiuretic hormone
Acute dyspnea is a major symptom of cardiac and
pulmonary pathology frequently leading to hospital
admission. Systemic biomarkers, such as cardiac troponins
and B-type natriuretic peptides (BNPs), are useful tools
in the diagnostic work-up and risk stratification of
patients with acute coronary heart disease and heart failure
], but the clinical application of biochemical
markers in acute exacerbation of chronic obstructive
pulmonary disease (AECOPD) is more uncertain due to
lack of validation of potential candidates [
Copeptin is a novel biomarker that could prove
helpful in the differential diagnosis and risk evaluation
of patients with acute dyspnea. The function of
copeptin is unknown, but the molecule is derived
from the 39-amino acid C-terminal fragment of the
arginine-vasopressin (AVP) precursor molecule,
prepro-vasopressin. Copeptin and AVP are released in
equimolar amounts and plasma levels correlate well
]. Thus, copeptin plasma concentrations are most
likely regulated by the same mechanisms that have
been established for AVP. Under normal conditions
AVP secretion is regulated according to plasma
osmolality by osmoreceptors in the hypothalamus, but
several strong non-osmotic pathways also exist [
particular, arterial under-filling, as observed during
heart failure, stimulates AVP secretion via
baroreceptors in the carotid sinus and the aortic arch [
Pulmonary disorders, including COPD are also associated
with elevated AVP levels, possibly due to impaired
gas exchange or activation of baroreceptors [
the mechanism is not clear. In addition, AVP
secretion is increased as part of a general stress response
. While analytical challenges and stability issues
have made reliable measurements of circulating AVP
difficult to achieve [
], copeptin is easily measured
and stable in plasma and serum for at least 7 days in
room temperature and over several freeze and thaw
]. The prognostic value of copeptin has
already been studied in several medical conditions.
Previous studies have found increased copeptin
concentrations to be associated with poor prognosis in
sepsis and hemorrhagic shock [
], and chronic HF [
]. In patients
with lower respiratory tract infections, copeptin
predicted mortality more accurately than C-reactive
protein (CRP) and leucocyte count [
patients admitted to hospital with acute dyspnea of
various etiologies, copeptin was found to be a strong
prognostic marker with superior accuracy compared
to BNP and NT-proBNP [
]. The aim of the present
study was to compare the prognostic and diagnostic
properties of copeptin and N-terminal pro-hormone
of BNP (NT-proBNP) in acute HF and AECOPD.
Akershus cardiac examination (ACE) 2 study
The Akershus Cardiac Examination (ACE) 2 Study was
designed to assess the diagnostic and prognostic value of
circulating biomarkers in patients admitted with acute
dyspnea to Akershus University Hospital, Lørenskog,
Norway. The primary aim of the ACE 2 study was to
analyze the prognostic properties of secretoneurin, and a
minimum sample size of 350 patients was originally
calculated by power analysis for this purpose [
method of patient recruitment and data collection has
also been described in detail previously [
over the age of 18 years were eligible for inclusion
during the first 24 h of admission if acute dyspnea was the
primary cause for hospitalization as evaluated by the
emergency department physician. Exclusion criteria were
dementia and other causes precluding informed patient
consent, disseminated malignant disease, acute
myocardial infarction or coronary intervention, major surgery
within the last 2 weeks, incomplete study blood
sampling, and hemoglobin <10 g/dL. Consecutive patients
were enrolled between 8 am and 2 pm Monday to
Thursday. Clinical information was obtained from
physicians on call, hospital records, and directly from the
patients by dedicated study personnel who used
standardized questionnaires. Echocardiography and
spirometry results were registered from hospital records. The
ACE 2 study was approved by the Norwegian Regional
Committees for Medical and Health Research Ethics
(REC) South East (#5.2008.2832) and conducted in
agreement with the Declaration of Helsinki. All
participants provided written informed consent prior to study
Adjudication of diagnosis and outcome
The final diagnosis of the index hospitalization was
established by two senior physicians working independently of
each other, and discordant diagnoses were resolved by
consensus. The two members of the adjudication
committee had no knowledge of study biomarker levels, but they
had access to all medical records, including follow-up data
and cardiac biomarker measurements such as
NTproBNP and troponin T that were ordered by the treating
physician. Patients were first classified into acute HF and
non-HF related dyspnea, and then patients in the non-HF
group were evaluated with respect to the AECOPD
diagnosis. The acute HF diagnosis was determined by the
European Society of Cardiology criteria [
], and the
AECOPD diagnosis was based on the criteria defined by
the Global initiative for Chronic Obstructive Lung Disease
]. Discordant diagnoses were resolved by
consensus. Survival status was recorded from electronic
hospital records, which are synchronized with Statistics
Norway, until the end of follow-up November 1st, 2012.
Standard biochemical work-up and arterial blood gas
measurements were collected at admission. Glomerular
filtration rate (GFR) was estimated by the Chronic
Kidney Disease Epidemiology Collaboration (CKD-EPI)
formula. Study blood sampling was performed by
venipuncture and uniformly processed throughout the
study period. Copeptin, N-terminal pro-B-type
natriuretic peptide (NT-proBNP) and high-sensitivity cardiac
troponin T (hs-TnT) were measured in samples
obtained <24 h after hospital admission by commercially
available assays: B-R-A-H-M-S Kryptor Copeptin assay
by Thermo Fisher Scientific Inc., Clinical Diagnostics,
BRAHMS GmbH, 16,761 Hennigsdorf, Germany; and
proBNP II and troponin T hs STAT assays by Roche
Diagnostics, Penzberg, Germany. Copeptin and hs-TnT
were measured in serum while NT-proBNP was
analyzed in plasma samples. The copeptin assay had a
detection limit of 0.9 pmol/L, a functional sensitivity
(inter-analysis variation <20%) above 2.0 pmol/L, and a
normal reference range (2.5–97.5 percentile) of 0.9–
14.9 pmol/L for healthy adults.
We report continuous variables as mean (± standard
deviation [SD]) or median (quartile [Q] 1–3) depending on
variable distribution. Differences between groups were
compared by Student’s t test or Mann-Whitney U tests
as appropriate. Binary data were compared by the
chisquare test and are presented as absolute numbers and
percentages. Positively skewed variables, including
biomarkers, were log transformed by the natural logarithm
to approach normal distribution and to reduce the effect
of outliers in regression analysis. Variables associated
with copeptin concentration were explored by
Spearman’s rank correlation coefficient (rho) and linear
regression analysis, and independent associations were
determined by multivariate linear regression using
stepwise forward selection of variables. Patient survival
stratified by admission copeptin and NT-proBNP
quartiles was analyzed by Kaplan-Meier plots and compared
by the log-rank test. We identified factors associated
with mortality by univariate Cox proportional hazard
regression analysis. A basic multivariate Cox model of
independent risk factors excluding biomarkers was
constructed by stepwise forward selection based on the
likelihood ratio criterion. The independent prognostic effect
of each biomarker was determined by adjusting for the
variables in the basic clinical risk model. The area under
receiver operating curves (ROC-AUC) was used to
ascertain the diagnostic and prognostic accuracies of
biomarkers, while the value of adding biomarkers to the
basic clinical risk models was investigated by calculating
the category free net reclassification index (NRI).
ROCAUCs are presented with 95% confidence interval (CI)
computed by bootstrap using 5000 iterations. We
considered p < 0.05 to be statistically significant and
statistical analyses were performed using SPSS for Windows
version 22.0 (SPSS, Armonk, NY), STATA version 14
(Stata Corp LP, TX, USA), and R 3.3.3 (R Foundation for
Statistical Computing, Vienna, Austria). NRI was
calculated using the R package PredictABEL.
In total, 314 of 468 eligible patients were included in the
ACE 2 Study from June 2009 until November 2010. Acute
HF was determined to be the primary cause of dyspnea in
143 patients, while 84 patients were diagnosed with
AECOPD (Fig. 1). Among patients with dyspnea not
related to acute HF or AECOPD (n = 87) the most frequent
diagnoses were pneumonia (27/87), asthma (16/87), and
pulmonary embolism (10/87). Median time from
hospitalization to adjudication of diagnosis was 464 days
(Q 1–3304–705). The two members of the adjudication
committee reached the same diagnosis in 95% (298/314)
of the cases, while the remaining 5% (16/324) were
resolved by consensus. The baseline characteristics of acute
HF and AECOPD patients were consistent with the
respective diagnosis (Table 1). Among patients diagnosed
with acute HF, chronic HF was previously recognized in
61%, and 43% also had a history of COPD. In the
AECOPD group, all patients were previously diagnosed
with COPD and the prevalence of chronic HF was 11%.
Copeptin concentrations and relation to prognosis
The prognostic properties of copeptin were analyzed in
AECOPD and acute HF separately. After a median
follow-up of 2.2 years (813 [356–996] days), 46% (66/
143) of HF patients and 42% (35/84) of AECOPD
patients had died. According to Kaplan-Meier estimates
(Fig. 2) the risk of mortality during follow-up increased
among acute HF patients if copeptin or NT-proBNP
levels were elevated on hospital admission (p < 0.0001
by the log-rank test for both biomarkers). In contrast,
only copeptin levels were associated with mortality
among patients diagnosed with AEOCPD (Fig. 2;
p < 0.0001 by the log-rank test). After adjustment for
basic clinical risk factors, as identified by univariate
screening (Additional file 1: Table S2), the risk of dying
increased by 72% in AECOPD (HR 1.72 [1.21–2.45],
p = 0.003) and 61% in acute HF (1.61 [1.25–2.09],
p < 0.001) per log (ln) unit increment of copeptin by
multivariate Cox analysis (Table 2). In comparison, one
log (ln) unit increase of NT-proBNP increased the risk
of mortality by 62% in acute HF (1.62 [1.27–2.06],
p < 0.001), while no significant predictive effect was
found in AECOPD (1.12 [0.88–1.42], p = 0.373). Neither
copeptin nor NT-proBNP were independently associated
with mortality in patients with dyspnea that was not
related to CODP or HF (Additional file 1: Table S3). When
copeptin and NT-proBNP was included in the same
model, the predictive effect of copeptin was significant
in patients with AECOPD (HR 1.79 [1.20–2.66],
p = 0.004), but not in patients with acute HF (1.30
[0.96–1.76], p = 0.091). When copeptin was added to the
basic clinical risk model, the category free net
reclassification index (NRI) was positive in AECOPD (NRI 0.60
[0.19–1.02], p = 0.004) and acute HF (0.39 [0.06–0.71],
p = 0.020). In the AECOPD group, the predicted risk of
mortality decreased in 67% of survivors and increased in
63% of non-survivors with the model that included
copeptin (Fig. 3). By ROC-AUC analysis, we could not
find any statistical difference between the prognostic
accuracy of copeptin and NT-proBNP in AECOPD
(ROCAUC 0.67 [0.55–0.79] vs. 0.56 [0.44–0.69], p = 0.111) or
acute HF (0.66 [0.57–0.75] vs. 0.67 [0.58–0.76],
p = 0.695). Adding NT-proBNP to the Cox regression
model that already included copeptin or vice versa did
not significantly alter the overall predictive accuracy of
the model, as determined by ROC-AUC or category free
NRI, in acute HF.
Copeptin concentrations and relation to diagnosis
At admission, a large portion of AECOPD patients (35%
[29/84]) and acute HF patients (64% [91/143] had
copeptin concentrations that exceeded the upper
reference limit (14.9 pmol/L) reported for healthy subjects by
the manufacturer of the current assay. The median
copeptin concentration was significantly higher among
acute HF patients compared to patients with AECOPD
and other causes of dyspnea (22.2 [10.2–47.9] vs. 8.8
[5.2–19.7] and 8.3 [4.3–18.2] pmol/L), but NT-proBNP
discriminated acute HF from non-HF related dyspnea
more accurately than copeptin (AUC 0.85 [95% CI 0.81–
0.89] vs. 0.71 [0.66–0.77], p < 0.0001). We did not find
any significant difference in the concentration of
copeptin or NT-proBNP between patients with AECOPD and
patients with other causes of dyspnea not related to HF.
By multivariate linear regression analysis across all
groups (Additional file 1: Table S1) increased copeptin
concentrations were independently associated with
increased hs-TnT, NT-proBNP, Na+, male gender and
reduced eGFR (r2 = 0.51). The correlation between
copeptin and individual independent covariates were
moderate for NT-proBNP (rho 0.60), hs-TNT (0.55),
and eGFR (−0.52); and weak for male gender (0.27) and
Na+ (0.24). While low Na+ levels were associated with
lower levels of copeptin (Additional file 1: Figure S1),
copeptin concentrations were measurable also among
patients with hyponatremia (Na+ concentrations
<137 mmol/L) in AECOPD (7.6 [2.7–16.0]) and acute
HF (18.2 [6.3–52.6] pmol/L).
In this prospective observational study, we found
copeptin to be a strong prognostic marker in both AECOPD
and acute HF, while NT-proBNP predicted mortality
only among acute HF patients. On the other hand,
NTproBNP concentrations on admission were superior to
copeptin concentrations to separate patients with acute
HF from patients with non-HF related dyspnea.
Copeptin (pmol/L) 8.8 (5.2–19.7) 22.2 (10.2–47.9) 8.3 (4.3–18.2) <0.001
Continuous variables are presented as mean ± standard deviation or median (quartile 1–3). Binary variables are presented as absolute numbers and percentages
Abbreviations: ACEi angiotensin-converting-enzyme inhibitor, AECOPD Acute exacerbation of chronic obstructive pulmonary disease, ARB angiotensin II receptor
blocker, BMI Body mass index, CRP C-reactive protein, eGFR estimated glomerular filtration rate (CKD-EPI), FEV1 forced expiratory volume in one second, FVC forced
vital capacity, HF heart failure, hs-TnT high sensitivity troponin T, LVEF left ventricular ejection fraction, n.a. not applicable, NT-proBNP N-terminal pro-B-type
natriuretic peptide, NYHA New York Heart Association, MAP Mean arterial pressure
*P for difference between AECOPD and acute HF
aMissing data >10%
bMissing data >85%
Sparse data exist concerning the prognostic value of
copeptin in AECOPD. One previous study found that
copeptin predicted mortality in a mixed population with
lower respiratory tract infection, but the majority of
patients in that study suffered from community-acquired
pneumonia, and only 60 of 543 patients had AECOPD
]. Another study found increasing levels of copeptin
to be associated with poor prognosis in AECOPD when
using a composite outcome of re-hospitalization and
]; however, composite outcomes are associated
with uncertainty with respect to the association with
individual components of the outcome [
]. A recent
multicenter study found that copeptin measured in
stable-state COPD predicted two-year mortality
independently of selected pulmonary risk factors, and
recommended a new risk assessment index including
]. Finally, a newly published multicenter
study of AECOPD patients did not find any association
between copeptin and a short-term (30 days) composite
outcome that included mortality, transfer to the
intensive care unit, or a new visit to the emergency room.
Notably, patients who required immediate intensive care
unit monitoring and/or assisted ventilation (invasive or
non-invasive) were excluded from the study and only 14
of 277 included patients died [
]. To clarify the
prognostic properties of copeptin with respect to mortality in
(n = 87)
73 ± 18
COPD in the acute setting we categorized unselected
patients with acute dyspnea by established guidelines
under the scrutiny of two experts working independently
and analyzed the prognostic properties of copeptin in
AECOPD and acute HF separately. From the results of
our study we confirm that copeptin is a strong predictor
of two-year mortality in AECOPD independently of
other pulmonary and cardiac risk factors.
The prognostic utility of natriuretic peptides in COPD
is controversial. In agreement with the results from one
previous study [
] we did not find any predictive value
of NT-proBNP regarding mortality in AECOPD.
Nevertheless, other studies have indicated that NT-proBNP
could be a useful prognostic marker in COPD [
The conflicting results concerning the prognostic value
of NT-proBNP in different COPD cohorts may relate to
misclassification of diagnosis or differing prevalence of
cardiac complications and comorbidities associated with
NT-proBNP and mortality, such as pulmonary
], cor pulmonale [
], and left ventricular
]. As no specific index can be used to
diagnose AECOPD or acute HF [
]. we stratified
our patients according to the diagnosis made by an
adjudication committee, which is considered to be the
“goldstandard” strategy in order to avoid misclassification. In
addition, our adjudication committee classified patients
more uniformly than previous adjudication committees
in similar studies [
]. In our AECOPD cohort, only
nine patients (11%) had a history of heart failure and the
median LVEF was normal (60% [Q1–3 50–60]),
indicating low prevalence of cardiac dysfunction. Thus, our
results show that copeptin is a strong prognostic marker
independent of cardiac pathology and support the theory
that the prognostic value of NT-proBNP in COPD is
related to cardiac complications and comorbidities.
As the ACE 2 Study was moderate in size, the negative
result for NT-proBNP in AECOPD could also be
explained by low statistical power. However, no trend for
increasing mortality by NT-proBNP categories was
observed in Kaplan-Meier survival plots (Fig. 2). We could
not find a statistical significant difference between the
prognostic accuracy of copeptin and NT-proBNP by
Median follow-up time period: 813 [Q1–3356–996] days
Abbreviations: BMI Body mass index, CI confidence interval, COPD chronic obstructive pulmonary disease, hs-TnT high sensitivity troponin T, HR hazard ratio, n.s
not statistically significant, NT-proBNP N-terminal pro-B-type natriuretic peptide, vs. versus
ROC-AUC in AECOPD, in contrast to the results
obtained by Cox proportional hazard regression analysis,
but this inconsistency probably relates to inferior
statistical properties when comparing predictors by
ROCAUC as opposed to regression analysis [
analyses found copeptin, but not NT-proBNP, to reclassify a
significant proportion of patients into their correct risk
strata on top of a basic clinical model. This emphasizes
the superior prognostic value of copeptin over
NTproBNP levels in AECOPD. Accordingly; our data
support copeptin as the preferred prognostic biomarker
concerning mortality in patients with AECOPD.
The prognostic accuracies of copeptin and
NTproBNP seem comparable in HF. In previous studies of
chronic HF, copeptin has been associated with
shortand long-term prognostic outcomes independently of
other risk factors including natriuretic peptides, and
in some of these studies copeptin also predicted the
outcome with higher accuracy than BNP and
]. In our study, we found copeptin to
be a strong predictor of mortality in acute HF
patients independently of basic risk factors, but after
adjustment for NT-proBNP the prognostic effect of
copeptin by Cox regression was not significant (Table
2). In contrast, we did not find any significant
difference between the prognostic accuracy of copeptin and
NT-proBNP estimated by ROC-AUC or improvement
in the overall predictive accuracy when NT-proBNP
was added to the multivariate Cox regression model
already including copeptin. The most likely
explanation for these findings is that copeptin and
NTproBNP carry much of the same prognostic
information in acute HF. Hence, copeptin also appears to be
a valid alternative to NT-proBNP with respect to
mortality risk evaluation in acute HF.
NT-proBNP concentrations were superior to copeptin
concentrations for the discrimination of acute HF from
other causes of dyspnea in our patients. This is not
surprising from a theoretical viewpoint as NT-proBNP is
released mainly as a result of myocardial stretch [
while copeptin release most likely is stimulated by the
same mechanisms known to stimulate AVP secretion
that are less specific for heart failure [
]. The finding
that NT-proBNP is a better diagnostic marker of acute
HF than copeptin is in line with our main finding that
copeptin is a better prognostic marker than NT-proBNP
in AECOPD patients.
The mechanisms responsible for increased copeptin
release in AECOPD are unclear. The median
concentration of copeptin found in AECOPD (8.8 [5.2–19.7])
is higher than what has been reported in healthy
subjects recruited from the general population (3.7–
4.2 pmol/L) [
]. A functioning osmotic
regulation of copeptin release is indicated by the positive
correlation between copeptin and Na+ concentrations
in our patients (Additional file 1: Figure S1), but
contrary to what is expected under normal osmotic
regulation , we found that copeptin is not clearly
suppressed among AECOPD or acute HF patients
with Na+ concentrations <137 mmol/L (7.6 [2.7–16.0]
and 18.2 [6.3–52.6] pmol/L, respectively). The missing
suppression of copeptin among hyponatremic patients
suggest the presence of an non-osmotic stimulation of
copeptin and AVP release that could also explain the
high prevalence of hyponatremia in AECOPD (27%)
and acute HF (20%) previously documented in the
ACE 2 Study [
]. In HF patients, arterial
underfilling is a strong stimulant of non-osmotic copeptin
and AVP release via baroreceptors [
], but this
pathway seem less likely in AECOPD patients with close
to normal cardiac function. Another relevant question
is whether the concentration of copeptin increases
during AECOPD compared to stable-state COPD.
Interestingly, one previous study of COPD patients
could not find any difference between copeptin levels
in stable-state and exacerbations [
]. We were,
however, not able to explore this question further as
stable-state copeptin measures were not included in
the ACE 2 study design. Clearly, further studies are
needed to explore the mechanisms that stimulate
copeptin and AVP secretion in COPD.
Copeptin is a strong prognostic marker in patients with
acute exacerbation of chronic obstructive pulmonary
disease (AECOPD) and acute heart failure (HF), while
NT-proBNP concentrations predict mortality only
among patients with acute HF. Accordingly, copeptin
could be preferable to NT-proBNP for risk stratification
in AECOPD and mixed populations that include both
AECOPD and acute HF patients. Copeptin
concentrations are significantly higher in patients with acute HF
compared to other etiologies of acute dyspnea, but
NTproBNP is superior to copeptin for diagnosing HF in the
Additional file 1: Table S1. Linear regression for log (ln) copeptin
(n = 314). Table S2. Univariate proportional Cox regression analysis.
Table S3. Multivariate proportional Cox regression analysis for the
nonHF, non-AECOPD group. Figure S1. Correlation between copeptin and
Na+. (DOCX 267 kb)
ACE Study: Akershus Cardiac Examination Study; AECOPD: Acute
exacerbation of chronic obstructive pulmonary disease; CI: Confidence
interval; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration;
COPD: Chronic obstructive pulmonary disease; CRP: C-reactive protein;
eGFR: estimated glomerular filtration rate; GOLD: Global initiative for Chronic
Obstructive Lung Disease; HF: Heart failure; HR: Hazard ratio; hs-TnT:
Highsensitivity troponin T; LVEF: Left ventricular ejection fraction; NRI: Net
reclassification index; NT-proBNP: N-terminal pro-hormone of B-type
natriuretic peptide; Q: Quartile; ROC-AUC: Area under receiver operating curves;
SD: Standard deviation; Vs: versus
We would like to acknowledge the contribution by the Clinical Trail Unit,
Division of Medicine, Akershus University Hospital and Vigdis Bakkelund, BSc;
Marit Holmefjord Pedersen, BSc; and Annika Lorentzen, BSc with all aspects
of the ACE 2 Study. We also thank physicians and nurses in the Division of
Medicine and acknowledge the Department of Medical Biochemistry,
Akershus University Hospital for laboratory analyses.
Akershus University Hospital and the Research Council of Norway funded
the ACE 2 Study. Thermo Fisher Scientific, Clinical Diagnostics, BRAHMS
GmbH 16,761 Hennigsdorf, Germany, Tel: +49–3302 - 883 – 0 provided
copeptin reagents free of charge for this study. NT-proBNP kits were
supplied at reduced price by Roche Diagnostics. The sponsors had no
role in any of the following: design and conduct of the study, collection,
management, analysis and interpretation of the data, or preparation,
review and approval of the manuscript.
Availability of data and materials
Due to ethical restrictions related to patient privacy, raw data are only
available upon request, subject to standard approval from the data
custodian: Dr. Helge Røsjø ().
JAW and TO had full access to all data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis. GC, TO,
and HR designed the clinical studies. JB, ADH, and HR were engaged in data
acquisition, HS was responsible for the biochemical analyses, while JAW, JB,
IF, SN, HR, and TO contributed to analysis and/or interpretation of data. All
authors have critically revised the manuscript and have approved the final
Ethics approval and consent to participate
The ACE 2 study was approved by the Norwegian Regional Committees for
Medical and Health Research Ethics (REC) South East (#5.2008.2832) and
conducted in agreement with the Declaration of Helsinki. All participants
provided written informed consent prior to study enrolment.
Consent for publication
JAW has received consultancy and speaker honoraria from Otsuka
Pharmaceuticals Europe Ltd. TO has received consultancy and speaker
honoraria from Abbott Diagnostics and Roche Diagnostics. HR has received
speaker honoraria from Novartis. All other authors declare no competing
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1. de Lemos JA , Morrow DA , Bentley JH , Omland T , Sabatine MS , McCabe CH , Hall C , Cannon CP , Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes . N Engl J Med . 2001 ; 345 : 1014 - 21 .
2. Bettencourt P. NT-proBNP and BNP: biomarkers for heart failure management . Eur J Heart Fail . 2004 ; 6 : 359 - 63 .
3. Kragelund C , Gronning B , Kober L , Hildebrandt P , Steffensen R. N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease . N Engl J Med . 2005 ; 352 : 666 - 75 .
4. Koutsokera A , Stolz D , Loukides S , Kostikas K. Systemic biomarkers in exacerbations of COPD: the evolving clinical challenge . Chest . 2012 ; 141 : 396 - 405 .
5. Christ-Crain M , Fenske W. Copeptin in the diagnosis of vasopressindependent disorders of fluid homeostasis . Nat Rev Endocrinol . 2016 ;
6. Schrier RW , Berl T , Anderson RJ . Osmotic and nonosmotic control of vasopressin release . Am J Phys . 1979 ; 236 : F321 - 32 .
7. Robertson GL , Shelton RL , Athar S. The osmoregulation of vasopressin . Kidney Int . 1976 ; 10 : 25 - 37 .
8. Farber MO , Roberts LR , Weinberger MH , Robertson GL , Fineberg NS , Manfredi F . Abnormalities of sodium and H2O handling in chronic obstructive lung disease . Arch Intern Med . 1982 ; 142 : 1326 - 30 .
9. de Leeuw PW , Dees A . Fluid homeostasis in chronic obstructive lung disease . Eur Respir J Suppl . 2003 ; 46 : 33s - 40s .
10. Itoi K , Jiang YQ , Iwasaki Y , Watson SJ . Regulatory mechanisms of corticotropin-releasing hormone and vasopressin gene expression in the hypothalamus . J Neuroendocrinol . 2004 ; 16 : 348 - 55 .
11. Preibisz JJ , Sealey JE , Laragh JH , Cody RJ , Weksler BB . Plasma and platelet vasopressin in essential hypertension and congestive heart failure . Hypertension . 1983 ; 5 : I129 - 38 .
12. Morgenthaler NG , Struck J , Alonso C , Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin . Clin Chem . 2006 ; 52 : 112 - 9 .
13. Struck J , Morgenthaler NG , Bergmann A . Copeptin, a stable peptide derived from the vasopressin precursor, is elevated in serum of sepsis patients . Peptides . 2005 ; 26 : 2500 - 4 .
14. Morgenthaler NG , Muller B , Struck J , Bergmann A , Redl H , Christ-Crain M . Copeptin, a stable peptide of the arginine vasopressin precursor, is elevated in hemorrhagic and septic shock . Shock . 2007 ; 28 : 219 - 26 .
15. Khan SQ , Dhillon OS , O'Brien RJ , Struck J , Quinn PA , Morgenthaler NG , Squire IB , Davies JE , Bergmann A , Ng LL . C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester acute myocardial infarction peptide (LAMP) study . Circulation . 2007 ; 115 : 2103 - 10 .
16. Stoiser B , Mortl D , Hulsmann M , Berger R , Struck J , Morgenthaler NG , Bergmann A , Pacher R . Copeptin, a fragment of the vasopressin precursor, as a novel predictor of outcome in heart failure . Eur J Clin Investig . 2006 ; 36 : 771 - 8 .
17. Neuhold S , Huelsmann M , Strunk G , Stoiser B , Struck J , Morgenthaler NG , Bergmann A , Moertl D , Berger R , Pacher R . Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-B-type natriuretic peptide in patients with chronic heart failure: prediction of death at different stages of the disease . J Am Coll Cardiol . 2008 ; 52 : 266 - 72 .
18. Voors AA , von Haehling S , Anker SD , Hillege HL , Struck J , Hartmann O , Bergmann A , Squire I , van Veldhuisen DJ , Dickstein K , Investigators O . Cterminal provasopressin (copeptin) is a strong prognostic marker in patients with heart failure after an acute myocardial infarction: results from the OPTIMAAL study . Eur Heart J . 2009 ; 30 : 1187 - 94 .
19. Muller B , Morgenthaler N , Stolz D , Schuetz P , Muller C , Bingisser R , Bergmann A , Tamm M , Christ-Crain M . Circulating levels of copeptin, a novel biomarker, in lower respiratory tract infections . Eur J Clin Investig . 2007 ; 37 : 145 - 52 .
20. Potocki M , Breidthardt T , Mueller A , Reichlin T , Socrates T , Arenja N , Reiter M , Morgenthaler NG , Bergmann A , Noveanu M , et al. Copeptin and risk stratification in patients with acute dyspnea . Crit Care . 2010 ; 14 : R213 .
21. Ottesen AH , Louch WE , Carlson CR , Landsverk OJ , Kurola J , Johansen RF , Moe MK , Aronsen JM , Hoiseth AD , Jarstadmarken H , et al. Secretoneurin is a novel prognostic cardiovascular biomarker associated with cardiomyocyte calcium handling . J Am Coll Cardiol . 2015 ; 65 : 339 - 51 .
22. Rosjo H , Dahl MB , Jorgensen M , Roysland R , Brynildsen J , Cataliotti A , Christensen G , Hoiseth AD , Hagve TA , Omland T. Influence of glycosylation on diagnostic and prognostic accuracy of N-terminal pro-B-type natriuretic peptide in acute dyspnea: data from the Akershus cardiac examination 2 study . Clin Chem . 2015 ; 61 : 1087 - 97 .
23. Winther JA , Brynildsen J , Hoiseth AD , Folling I , Brekke PH , Christensen G , Hagve TA , Verbalis JG , Omland T , Rosjo H. Prevalence and prognostic significance of Hyponatremia in patients with acute exacerbation of chronic obstructive pulmonary disease: data from the Akershus cardiac examination (ACE) 2 study . PLoS One . 2016 ; 11 : e0161232 .
24. Roysland R , Pervez MO , Pedersen MH , Brynildsen J , Hoiseth AD , Hagve TA , Rosjo H , Omland T. Diagnostic and prognostic properties of Osteoprotegerin in patients with acute Dyspnoea: observations from the Akershus cardiac examination (ACE) 2 study . PLoS One . 2016 ; 11 : e0160182 .
25. McMurray JJ , Adamopoulos S , Anker SD , Auricchio A , Bohm M , Dickstein K , Falk V , Filippatos G , Fonseca C , Gomez-Sanchez MA , et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the heart failure association (HFA) of the ESC . Eur Heart J . 2012 ; 33 : 1787 - 847 .
26. Global Initiative for Chronic Obstructive Lung Disease (GOLD) . Global strategy for Diagnosis, Management and Prevention of Chronic Pulmonary Disease [http://www.goldcopd.org/].
27. Stolz D , Christ-Crain M , Morgenthaler NG , Leuppi J , Miedinger D , Bingisser R , Muller C , Struck J , Muller B , Tamm M. Copeptin , C-reactive protein, and procalcitonin as prognostic biomarkers in acute exacerbation of COPD . Chest. 2007 ; 131 : 1058 - 67 .
28. Freemantle N , Calvert M , Wood J , Eastaugh J , Griffin C . Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA. 2003 ; 289 : 2554 - 9 .
29. Boeck L , Soriano JB , Brusse-Keizer M , Blasi F , Kostikas K , Boersma W , Milenkovic B , Louis R , Lacoma A , Djamin R , et al. Prognostic assessment in COPD without lung function: the B-AE-D indices . Eur Respir J . 2016 ; 47 : 1635 - 44 .
30. Dres M , Hausfater P , Foissac F , Bernard M , Joly LM , Sebbane M , Philippon AL , Gil-Jardine C , Schmidt J , Maignan M , et al. Mid-regional proadrenomedullin and copeptin to predict short-term prognosis of COPD exacerbations: a multicenter prospective blinded study . Int J Chron Obstruct Pulmon Dis . 2017 ; 12 : 1047 - 56 .
31. Stolz D , Breidthardt T , Christ-Crain M , Bingisser R , Miedinger D , Leuppi J , Mueller B , Tamm M , Mueller C . Use of B-type natriuretic peptide in the risk stratification of acute exacerbations of COPD . Chest. 2008 ; 133 : 1088 - 94 .
32. Chang CL , Robinson SC , Mills GD , Sullivan GD , Karalus NC , McLachlan JD , Hancox RJ . Biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of COPD . Thorax. 2011 ; 66 : 764 - 8 .
33. Hoiseth AD , Omland T , Hagve TA , Brekke PH , Soyseth V . NT-proBNP independently predicts long term mortality after acute exacerbation of COPD - a prospective cohort study . Respir Res . 2012 ; 13 : 97 .
34. Leuchte HH , Baumgartner RA , Nounou ME , Vogeser M , Neurohr C , Trautnitz M , Behr J . Brain natriuretic peptide is a prognostic parameter in chronic lung disease . Am J Respir Crit Care Med . 2006 ; 173 : 744 - 50 .
35. Bozkanat E , Tozkoparan E , Baysan O , Deniz O , Ciftci F , Yokusoglu M. The significance of elevated brain natriuretic peptide levels in chronic obstructive pulmonary disease . J Int Med Res . 2005 ; 33 : 537 - 44 .
36. Gariani K , Delabays A , Perneger TV , Agoritsas T . Use of brain natriuretic peptide to detect previously unknown left ventricular dysfunction in patients with acute exacerbation of chronic obstructive pulmonary disease . Swiss Med Wkly . 2011 ; 141 : w13298 .
37. Inoue Y , Kawayama T , Iwanaga T , Aizawa H . High plasma brain natriuretic peptide levels in stable COPD without pulmonary hypertension or cor pulmonale . Intern Med . 2009 ; 48 : 503 - 12 .
38. Abroug F , Ouanes-Besbes L , Nciri N , Sellami N , Addad F , Hamda KB , Amor AB , Najjar MF , Knani J . Association of left-heart dysfunction with severe exacerbation of chronic obstructive pulmonary disease: diagnostic performance of cardiac biomarkers . Am J Respir Crit Care Med . 2006 ; 174 : 990 - 6 .
39. Wang CS , FitzGerald JM , Schulzer M , Mak E , Ayas NT . Does this dyspneic patient in the emergency department have congestive heart failure? JAMA. 2005 ; 294 : 1944 - 56 .
40. Januzzi JL Jr, Camargo CA , Anwaruddin S , Baggish AL , Chen AA , Krauser DG , Tung R , Cameron R , Nagurney JT , Chae CU , et al. The N-terminal pro-BNP investigation of dyspnea in the emergency department (PRIDE) study . Am J Cardiol . 2005 ; 95 : 948 - 54 .
41. McCullough PA , Nowak RM , McCord J , Hollander JE , Herrmann HC , Steg PG , Duc P , Westheim A , Omland T , Knudsen CW , et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from breathing not properly (BNP) multinational study . Circulation . 2002 ; 106 : 416 - 22 .
42. Vickers AJ , Cronin AM , Begg CB . One statistical test is sufficient for assessing new predictive markers . BMC Med Res Methodol . 2011 ; 11 : 13 .
43. Omland T , Hagve TA . Natriuretic peptides: physiologic and analytic considerations . Heart Fail Clin . 2009 ; 5 : 471 - 87 .
44. Reichlin T , Hochholzer W , Stelzig C , Laule K , Freidank H , Morgenthaler NG , Bergmann A , Potocki M , Noveanu M , Breidthardt T , et al. Incremental value of copeptin for rapid rule out of acute myocardial infarction . J Am Coll Cardiol . 2009 ; 54 : 60 - 8 .
45. Fenske W , Stork S , Blechschmidt A , Maier SG , Morgenthaler NG , Allolio B. Copeptin in the differential diagnosis of hyponatremia . J Clin Endocrinol Metab . 2009 ; 94 : 123 - 9 .